Quinazoline derivatives as tyrosine kinase inhibitors

ABSTRACT

The invention concerns quinazoline derivatives of the Formula I: 
     
       
         
         
             
             
         
       
     
     wherein each of R 1 , R 2 , W, X 1 , X 2 , Z, a and b are as defined in the description; processes for their preparation; pharmaceutical compositions containing them and their use in the manufacture of a medicament for providing an anti-proliferative effect. The quinazoline derivatives of Formula I are expected to be useful in the treatment of diseases such as certain cancers mediated by erbB receptor tyrosine kinases, particularly EGFR tyrosine kinase.

The invention concerns certain novel quinazoline derivatives, orpharmaceutically acceptable salts, or pharmaceutically acceptable estersthereof, which possess anti-tumour activity and are accordingly usefulin methods of treatment of the human or animal body. The invention alsoconcerns processes for the manufacture of said quinazoline derivatives,to pharmaceutical compositions containing them and to their use intherapeutic methods, for example in the manufacture of medicaments foruse in the prevention or treatment of solid tumour disease in awarm-blooded animal such as man.

Many of the current treatment regimes for diseases resulting from theabnormal regulation of cellular proliferation such as psoriasis andcancer, utilise compounds that inhibit DNA synthesis and cellularproliferation. To date, compounds used in such treatments are generallytoxic to cells however their enhanced effects on rapidly dividing cellssuch as tumour cells can be beneficial. Alternative approaches to thesecytotoxic anti-tumour agents are currently being developed, for exampleselective inhibitors of cell signalling pathways. These types ofinhibitors are likely to have the potential to display an enhancedselectivity of action against tumour cells and so are likely to reducethe probability of the therapy possessing unwanted side effects.

Eukaryotic cells are continually responding to many diverseextracellular signals that enable communication between cells within anorganism. These signals regulate a wide variety of physical responses inthe cell including proliferation, differentiation, apoptosis andmotility. The extracellular signals take the form of a diverse varietyof soluble factors including growth factors as well as paracrine andendocrine factors. By binding to specific transmembrane receptors, theseligands integrate the extracellular signal to the intracellularsignalling pathways, therefore transducing the signal across the plasmamembrane and allowing the individual cell to respond to itsextracellular signals. Many of these signal transduction processesutilise the reversible process of the phosphorylation of proteins thatare involved in the promotion of these diverse cellular responses. Thephosphorylation status of target proteins is regulated by specifickinases and phosphatases that are responsible for the regulation ofabout one third of all proteins encoded by the mammalian genome. Asphosphorylation is such an important regulatory mechanism in the signaltransduction process, it is therefore not surprising that aberrations inthese intracellular pathways result in abnormal cell growth anddifferentiation and so promote cellular transformation (reviewed inCohen et al., Curr Opin Chem Biol, 1999, 3, 459-465).

It has been widely shown that a number of these tyrosine kinases aremutated to constitutively active forms and/or when over-expressed resultin the transformation of a variety of human cells. These mutated andover-expressed forms of the kinase are present in a large proportion ofhuman tumours (reviewed in Kolibaba et al., Biochimica et BiophysicaActa, 1997, 133, F217-F248). As tyrosine kinases play fundamental rolesin the proliferation and differentiation of a variety of tissues, muchfocus has centred on these enzymes in the development of novelanti-cancer therapies. This family of enzymes is divided into twogroups—receptor and non-receptor tyrosine kinases e.g. EGF Receptors andthe SRC family respectively. From the results of a large number ofstudies including the Human Genome Project, about 90 tyrosine kinasehave been identified in the human genome, of this 58 are of the receptortype and 32 are of the non-receptor type. These can be compartmentalisedin to 20 receptor tyrosine kinase and 10 non-receptor tyrosine kinasesub-families (Robinson et al, Oncogene, 2000, 19, 5548-5557).

The receptor tyrosine kinases are of particular importance in thetransmission of mitogenic signals that initiate cellular replication.These large glycoproteins, which span the plasma membrane of the cellpossess an extracellular binding domain for their specific ligands (suchas Epidermal Growth Factor (EGF) for the EGF Receptor). Binding ofligand results in the activation of the receptor's kinase enzymaticactivity that is encoded by the intracellular portion of the receptor.This activity phosphorylates key tyrosine amino acids in targetproteins, resulting in the transduction of proliferative signals acrossthe plasma membrane of the cell.

It is known that the erbB family of receptor tyrosine kinases, whichinclude EGFR, erbB2, erbB3 and erbB4, are frequently involved in drivingthe proliferation and survival of tumour cells (reviewed in Olayioye etal., EMBO J., 2000, 19, 3159). One mechanism in which this can beaccomplished is by overexpression of the receptor at the protein level,generally as a result of gene amplification. This has been observed inmany common human cancers (reviewed in Klapper et al., Adv. Cancer Res.,2000, 77, 25) such as breast cancer (Sainsbury et al., Brit. J. Cancer,1988, 58, 458; Guerin et al., Oncogene Res., 1988, 3, 21; Slamon et al.,Science, 1989, 244, 707; Klijn et al., Breast Cancer Res. Treat., 1994,29 73 and reviewed in Salomon et al., Crit. Rev. Oncol. Hematol., 1995,19, 183), non-small cell lung cancers (NSCLCs) including adenocarcinomas(Cerny et al., Brit. J. Cancer, 1986, 54, 265; Reubi et al., Int. J.Cancer, 1990, 45, 269; Rusch et al., Cancer Research, 1993, 53, 2379;Brabender et al, Clin. Cancer Res., 2001, 7, 1850) as well as othercancers of the lung (Hendler et al., Cancer Cells, 1989, 7, 347; Ohsakiet al., Oncol. Rep., 2000, 7, 603), bladder cancer (Neal et al., Lancet,1985, 366; Chow et al., Clin. Cancer Res., 2001, 7, 1957, Zhau et al.,Mol. Carcinog., 3, 254), oesophageal cancer (Mukaida et al., Cancer,1991, 68, 142), gastrointestinal cancer such as colon, rectal or stomachcancer (Bolen et al., Oncogene Res., 1987, 1, 149; Kapitanovic et al.,Gastroenterology, 2000, 112, 1103; Ross et al., Cancer Invest., 2001,19, 554), cancer of the prostate (Visakorpi et al., Histochem. J., 1992,24 481; Kumar et al., 2000, 32, 73; Scher et al., J. Natl. Cancer Inst.,2000, 92, 1866), leukaemia (Konaka et al., Cell, 1984, 37, 1035,Martin-Subero et al., Cancer Genet Cytogenet., 2001, 127, 174), ovarian(Hellstrom et al., Cancer Res., 2001, 61, 2420), head and neck (Shiga etal., Head Neck, 2000, 22, 599) or pancreatic cancer (Ovotny et al.,Neoplasma, 2001, 48, 188). As more human tumour tissues are tested forexpression of the erbB family of receptor tyrosine kinases it isexpected that their widespread prevalence and importance will be furtherenhanced in the future.

As a consequence of the mis-regulation of one or more of thesereceptors, it is widely believed that many tumours become clinicallymore aggressive and so correlate with a poorer prognosis for the patient(Brabender et al, Clin. Cancer Res., 2001, 7, 1850; Ross et al, CancerInvestigation, 2001, 19, 554, Yu et al., Bioessays, 2000, 22.7, 673). Inaddition to these clinical findings, a wealth of pre-clinicalinformation suggests that the erbB family of receptor tyrosine kinasesare involved in cellular transformation. This includes the observationsthat many tumour cell lines overexpress one or more of the erbBreceptors and that EGFR or erbB2 when transfected into non-tumour cellshave the ability to transform these cells. This tumourigenic potentialhas been further verified as transgenic mice that overexpress erbB2spontaneously develop tumours in the mammary gland. In addition to this,a number of pre-clinical studies have demonstrated thatanti-proliferative effects can be induced by knocking out one or moreerbB activities by small molecule inhibitors, dominant negatives orinhibitory antibodies (reviewed in Mendelsohn et al., Oncogene, 2000,19, 6550). Thus it has been recognised that inhibitors of these receptortyrosine kinases should be of value as a selective inhibitor of theproliferation of mammalian cancer cells (Yaish et al. Science, 1988,242, 933, Kolibaba et al, Biochimica et Biophysica Acta, 1997, 133,F217-F248; Al-Obeidi et al, 2000, Oncogene, 19, 5690-5701; Mendelsohn etal, 2000, Oncogene, 19, 6550-6565).

Recently the small molecule EGFR tyrosine kinase inhibitor, Iressa (alsoknown as gefitinib, and ZD1834) has been approved for use in thetreatment of advanced non-small cell lung cancer. Furthermore, findingsusing inhibitory antibodies against EGFR and erbB2 (c-225 andtrastuzumab respectively) have proven to be beneficial in the clinic forthe treatment of selected solid tumours (reviewed in Mendelsohn et al.,2000, Oncogene, 19, 6550-6565).

Amplification and/or activity of members of the erbB receptor tyrosinekinases have been detected and so have been implicated to play a role ina number of non-malignant proliferative disorders such as psoriasis(Ben-Bassat, Curr. Pharm. Des., 2000, 6, 933; Elder et al., Science,1989, 243, 811), benign prostatic hyperplasia (BPH) (Kumar et al., Int.Urol. Nephrol., 2000, 32, 73), atherosclerosis and restenosis (Bokemeyeret al., Kidney Int., 2000, 58, 549). It is therefore expected thatinhibitors of erbB receptor tyrosine kinases will be useful in thetreatment of these and other non-malignant disorders of excessivecellular proliferation.

European patent application EP 566 226 discloses certain4-anilinoquinazolines that are receptor tyrosine kinase inhibitors.

International patent applications WO 96/33977, WO 96/33978, WO 96/33979,WO 96/33980, WO 96/33981, WO 97/30034, WO 97/38994 disclose that certainquinazoline derivatives which bear an anilino substituent at the4-position and a substituent at the 6- and/or 7-position possessreceptor tyrosine kinase inhibitory activity.

European patent application EP 837 063 discloses aryl substituted4-aminoquinazoline derivatives carrying moiety containing an aryl orheteroaryl group at the 6- or 7-position on the quinazoline ring. Thecompounds are stated to be useful for treating hyperproliferativedisorders.

International patent applications WO 97/30035 and WO 98/13354 disclosecertain 4-anilinoquinazolines substituted at the 7-position are vascularendothelial growth factor receptor tyrosine kinase inhibitors.

WO 00/55141 discloses 6,7-substituted 4-anilinoquinazoline compoundscharacterised in that the substituents at the 6- and/or 7-position carrycertain ester groups.

WO 00/56720 discloses 6,7-dialkoxy-4-anilinoquinazoline compounds forthe treatment of cancer or allergic reactions.

WO01/21596 discloses the use of certain 4-anilinoquinazoline derivativesas aurora 2 kinase inhibitors.

WO 02/18351 and WO 02/18372 disclose certain 4-anilinoquinazolinecompounds substituted at the 6- and/or 7-position which are stated tohave an inhibitory effect upon signal transduction mediated by tyrosinekinases.

WO 02/41882 discloses 4-anilinoquinazoline compounds substituted at the6- and/or 7-position by a substituted pyrrolidinyl-alkoxy orpiperidinyl-alkoxy group.

We have now found that surprisingly certain quinazoline derivativessubstituted at the 7-position with a substituent containing certainsubstituted alkanoyl groups possess potent anti-tumour activity. Thecompounds of the present invention also generally possess high cellularpotency, and favourable physical properties, particularly solubility,which may provide advantages in the formulation and delivery of thecompound to patients. Many of the compounds of the invention possesfavourable DMPK properties, for example high bioavailability and/or highfree-plasma levels and/or advantageous half life and/or advantageousvolume of distribution and such properties are expected to provideimproved in-vivo efficacy and may reduce inter-patient variability inexposure to the compound compared to other EGFR tyrosine kinaseinhibitors such as gefitinib.

Furthermore, many of the compounds according to the present inventionare inactive or only weakly active in a hERG assay.

Without wishing to imply that the compounds disclosed in the presentinvention possess pharmacological activity only by virtue of an effecton a single biological process, it is believed that the compoundsprovide an anti-tumour effect by way of inhibition of one or more of theerbB family of receptor tyrosine kinases that are involved in the signaltransduction steps which lead to the proliferation of tumour cells. Inparticular, it is believed that the compounds of the present inventionprovide an anti-tumour effect by way of inhibition of EGFR tyrosinekinase.

Generally the compounds of the present invention possess potentinhibitory activity against the erbB receptor tyrosine kinase family,for example by inhibition of EGF and/or erbB2 and/or erbB4 receptortyrosine kinases, whilst possessing less potent inhibitory activityagainst other kinases, such as VEGF and KDR receptor tyrosine kinases.Furthermore, the compounds of the present invention possesssubstantially better potency against the EGFR tyrosine kinase over thatof the erbB2 tyrosine kinase. Accordingly, it may be possible toadminister a compound according to the present invention at a dose thatis sufficient to inhibit EGFR tyrosine kinase whilst having nosignificant effect upon erbB2 (or other) tyrosine kinases. The selectiveinhibition provided by the compounds according to the present inventionmay provide treatments for conditions mediated by EGFR tyrosine kinase,whilst reducing undesirable side effects that may be associated with theinhibition of other tyrosine kinases.

According to a first aspect of the invention there is provided aquinazoline derivative of the Formula I:

wherein:

R¹ is selected from hydrogen, hydroxy, (1-6C)alkoxy, (2-6C)alkenyloxy,(2-6C)alkynyloxy, or from a group of the formula:

Q²-X³-

wherein X³ is a direct bond or is O, and Q² is (3-7C)cycloalkyl,(3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-6C)alkyl, heterocyclyl orheterocyclyl-(1-6C)alkyl,

and wherein adjacent carbon atoms in any (2-6C)alkylene chain within aR¹ substituent are optionally separated by the insertion into the chainof a group selected from O, S, SO, SO₂, N(R³), CO, CH(OR³), CON(R³),N(R³)CO, SO₂N(R³), N(R³)SO₂, CH═CH and C≡C wherein R³ is hydrogen or(1-6C)alkyl,

and wherein any CH₂═CH— or HC≡C— group within a R¹ substituentoptionally bears at the terminal CH₂= or HC_-position a substituentselected from halogeno, carboxy, carbamoyl, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl anddi-[(1-6C)alkyl]amino-(1-6C)alkyl or from a group of the formula:

Q³-X⁴-

wherein X³ is a direct bond or is selected from CO and N(R⁴)CO, whereinR⁴ is hydrogen or (1-6C)alkyl, and Q⁴ is heterocyclyl orheterocyclyl-(1-6C)alkyl,

and wherein any CH₂ or CH₃ group within a R¹ substituent, other than aCH₂ group within a heterocyclyl ring, optionally bears on each said CH₂or CH₃ group one or more halogeno or (1-6C)alkyl substituents or asubstituent selected from hydroxy, cyano, amino, carboxy, carbamoyl,sulfamoyl, oxo, thioxo, (1-6C)alkoxy, (1-6C)alkylthio,(1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,(1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino,or from a group of the formula:

X⁵-Q⁴-

wherein X⁵ is a direct bond or is selected from O, S, SO, SO₂, N(R⁵),Co, CH(OR⁵), CON(R⁵), N(R⁵)CO, SO₂N(R⁵), N(R⁵)SO₂, C(R⁵)₂O, C(R⁵)₂S andC(R⁵)₂N(R⁵), wherein R⁵ is hydrogen or (1-6C)alkyl, and Q⁴ is(3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-6C)alkyl, heterocyclyl orheterocyclyl-(1-6C)alkyl,

and wherein any heterocyclyl group within a substituent on R¹ optionallybears one or more (for example 1, 2 or 3) substituents, which may be thesame or different, selected from halogeno, trifluoromethyl, cyano,nitro, hydroxy, amino, carboxy, carbamoyl, formyl, mercapto, sulfamoyl,(1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy,(2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio,(1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, N-(1-6C)alkylsulfamoyl,N,N-di-[(1-6C)alkyl]sulfamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,(1-6C)alkanesulfonylamino, and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino,or from a group of the formula:

X⁶-R⁶

wherein X⁶ is a direct bond or is selected from O, N(R⁷) and C(O),wherein R⁷ is hydrogen or (1-6C)alkyl, and R⁶ is halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, carboxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl,cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,di-[(1-6C)alkyl]amino-(1-6C)alkyl, (2-6C)alkanoylamino-(1-6C)alkyl,(1-6C)alkoxycarbonylamino-(1-6C)alkyl, carbamoyl-(1-6C)alkyl,N-(1-6C)alkylcarbamoyl-(1-6C)alkyl,N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl, (2-6C)alkanoyl-(1-6C)alkyl or(1-6C)alkoxycarbonyl-(1-6C)alkyl,

and wherein any heterocyclyl group within a substituent on R¹ optionallybears 1 or 2 oxo or thioxo substituents;

b is 1, 2, 3, 4 or 5;

each R², which may be the same or different, is selected from halogeno,cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulfamoyl,trifluoromethyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl,(1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio,(1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,(1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino and agroup of the formula:

X⁷-R⁸

wherein X⁷ is a direct bond or is selected from O and N(R⁹), wherein R⁹is hydrogen or (1-6C)alkyl, and R⁸ is halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,di-[(1-6C)alkyl]amino-(1-6C)alkyl, (2-6C)alkanoylamino-(1-6C)alkyl or(1-6C)alkoxycarbonylamino-(1-6C)alkyl;

-   -   Q¹ is piperidinyl;    -   a is 0, 1, 2, 3 or 4;

each W, which may be the same or different, is selected from halogeno,trifluoromethyl, cyano, nitro, hydroxy, oxo, amino, formyl, mercapto,(1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl,(1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,(2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:

X⁸-R¹⁰

wherein X⁸ is a direct bond or is selected from O, CO, SO₂ and N(R¹¹),wherein R¹¹ is hydrogen or (1-6C)alkyl, and R¹⁰ is halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,amino-(1-6C)alkyl, N-(1-6C)alkylamino-(1-6C)alkyl orN,N-di-[(1-6C)alkyl]amino-(1-6C)alkyl;

X¹ is selected from CO and SO₂;

X² is a group of the formula:

—(CR¹²R¹³)_(p)-(Q⁵)_(m)-(CR¹⁴R¹⁵)_(q)-

wherein m is 0 or 1, p is 0, 1, 2, 3 or 4 and q is 0, 1, 2, 3 or 4,

each of R¹², R¹³, R¹⁴ and R¹⁵, which may be the same or different, isselected from hydrogen, (1-6C)alkyl, amino, (1-6C)alkylamino anddi-[(1-6C)alkyl]amino, and Q⁵ is selected from (3-7C)cycloalkylene and(3-7C)cycloalkenylene,

and wherein any CH₂ or CH₃ group within an X² group, optionally bears oneach said CH₂ or CH₃ group one or more halogeno or (1-6C)alkylsubstituents or a substituent selected from hydroxy, cyano, amino,(1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino;

Z is selected from hydroxy, amino, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxy, (1-6C)alkylsulfonyl,(1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino and agroup of the formula:

Q⁶-X⁹-

-   -   wherein X⁹ is a direct bond or is selected from O, N(R¹⁶), SO₂        and SO₂N(R¹⁶), wherein R¹⁶ is hydrogen or (1-6C)alkyl, and Q⁶ is        (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-4C)alkyl,        (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl        or heterocyclyl-(1-4C)alkyl;

provided that when X⁹ is a direct bond, Q⁶ is heterocyclyl,

and provided that when m, p and q are all 0, then Z is heterocyclyl,

and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a Zsubstituent are optionally separated by the insertion into the chain ofa group selected from O, S, SO, SO₂, N(R¹⁷), CO, —C≡C— and —C≡C— whereinR¹⁷ is hydrogen or (1-6C)alkyl,

and wherein and wherein any CH₂ or CH₃ group within any Z group, otherthan a CH₂ group within a heterocyclyl ring, optionally bears on eachsaid CH₂ or CH₃ group one or more halogeno or (1-6C)alkyl substituentsor a substituent selected from hydroxy, cyano, amino, carboxy,carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,(1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino,

and wherein any heterocyclyl group within a Z substituent optionallybears one or more (for example 1, 2 or 3) substitutents which may be thesame or different, selected from halogeno, trifluoromethyl, cyano,nitro, hydroxy, amino, formyl, mercapto, (1-6C)alkyl, (2-6C)alkenyl,(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl,(1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,(2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:

X¹⁰-R¹⁸

wherein X¹⁰ is a direct bond or is selected from O, CO, SO₂ and N(R¹⁹),wherein R¹⁹ is hydrogen or (1-4C)alkyl, and R¹⁸ is halogeno-(1-4C)alkyl,hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl,amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyl andN,N-di-[(1-4C)alkyl]amino-(1-4C)alkyl;

provided that:

when the 4-anilino group in Formula I is 4-bromo-2-fluoroanilino or4-chloro-2-fluoroanilino and R¹ is hydrogen or (1-3C)alkoxy, then a is 0and Z is selected from hydroxy, amino, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxy, (1-6C)alkylsulfonyl,(1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, anda group of the formula Q⁶-X⁹-;

or a pharmaceutically acceptable salt, or a pharmaceutically acceptableester thereof.

In a particular embodiment of the invention there is provided aquinazoline derivative of the Formula I as defined above, or apharmaceutically acceptable salt thereof.

In this specification the generic term “alkyl” includes bothstraight-chain and branched-chain alkyl groups such as propyl, isopropyland tert-butyl, and (3-7C)cycloalkyl groups such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. However referencesto individual alkyl groups such as “propyl” are specific for thestraight-chain version only, references to individual branched-chainalkyl groups such as “isopropyl” are specific for the branched-chainversion only and references to individual cycloalkyl groups such as“cyclopentyl” are specific for that 5-membered ring only. An analogousconvention applies to other generic terms, for example (1-6C)alkoxyincludes methoxy, ethoxy, cyclopropyloxy and cyclopentyloxy,(1-6C)alkylamino includes methylamino, ethylamino, cyclobutylamino andcyclohexylamino, and di-[(1-6C)alkyl]amino includes dimethylamino,diethylamino, N-cyclobutyl-N-methylamino and N-cyclohexyl-N-ethylamino.

It is to be understood that, insofar as certain of the compounds ofFormula I defined above may exist in optically active or racemic formsby virtue of one or more asymmetric carbon atoms, the invention includesin its definition any such optically active or racemic form whichpossesses the above-mentioned activity. It is further to be understoodthat in the names of chiral compounds (R,S) denotes any scalemic orracemic mixture while (R) and (S) denote the enantiomers. In the absenceof (R,S), (R) or (S) in the name it is to be understood that the namerefers to any scalemic or racemic mixture, wherein a scalemic mixturecontains R and S enantiomers in any relative proportions and a racemicmixture contains R and S enantiomers in the ratio 50:50. The synthesisof optically active forms may be carried out by standard techniques oforganic chemistry well known in the art, for example by synthesis fromoptically active starting materials or by resolution of a racemic form.Similarly, the above-mentioned activity may be evaluated using thestandard laboratory techniques referred to hereinafter.

Suitable values for the generic radicals referred to above include thoseset out below.

A suitable value for any one of the ‘Q’ groups (for example Q², Q⁴ orQ⁶) when it is (3-7C)cycloalkyl or for the (3-7C)cycloalkyl group withina ‘Q’ or R group is, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl or bicyclo[2.2.1]heptyl and a suitable value forany one of the ‘Q’ groups (for example Q², Q⁴ or Q⁶) when it is(3-7C)cycloalkenyl or for the (3-7C)cycloalkenyl group within a ‘Q’group is, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl orcycloheptenyl. It is to be understood that reference to(3-7C)cycloalkylene used herein for Q⁵ refers to a divalent(3-7C)cycloalkane linking group, which group may be linked via differentcarbon atoms in the (3-7C)cycloalkylene ring, or which may be linked viaa single carbon atom in the (3-7C)cycloalkylene ring. Accordingly,reference to, for example, a “cyclopropylene” group includescycloprop-1,2-ylene and a cyclopropylidene group of the formula:

However references to an individual (3-7C)cycloalklene group such ascyclopropylidene are specific for that group only. A similar conventionis adopted for the (3-7C)cycloalkenylene groups represented by Q⁵.

A suitable value for the ‘Q’ groups, other than Q¹ (for example Q², Q³,Q⁴ or Q⁶) when it is heterocyclyl or for the heterocyclyl group within a‘Q’ group is a non-aromatic saturated (i.e. ring systems with themaximum degree of saturation) or partially saturated (i.e. ring systemsretaining some, but not the full, degree of unsaturation) 3 to 10membered monocyclic or bicyclic ring with up to five heteroatomsselected from oxygen, nitrogen and sulfur, which, unless specifiedotherwise, may be carbon or nitrogen linked, for example oxiranyl,oxetanyl, azetidinyl, tetrahydrofuranyl, 1,3-dioxolanyl,tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, pyrrolinyl, pyrrolidinyl,morpholinyl, tetrahydro-1,4-thiazinyl,1,1-dioxotetrahydro-1,4-thiazinyl, piperidinyl, homopiperidinyl,piperazinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl,dihydropyrimidinyl, tetrahydropyrimidinyl, tetrahydrothienyl,tetrahydrothiopyranyl, decahydroisoquinolinyl or decahydroquinolinyl,particularly tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl,morpholinyl, 1,4-oxazepanyl, thiamorpholinyl1,1-dioxotetrahydro-4H-1,4-thiazinyl, piperidinyl or piperazinyl, moreparticularly tetrahydrofuran-3-yl, tetrahydropyran-4-yl,tetrahydrothien—3-yl, tetrahydrothiopyran-4-yl, pyrrolidin-1-yl,pyrrolidin-2-yl, pyrrolidin-3-yl, morpholino, morpholin-2-yl,piperidino, piperidin-4-yl, piperidin-3-yl, piperidin-2-yl orpiperazin-1-yl. A nitrogen or sulfur atom within a heterocyclyl groupmay be oxidized to give the corresponding N or S oxide, for example1,1-dioxotetrahydrothienyl, 1-oxotetrahydrothienyl,1,1-dioxotetrahydrothiopyranyl or 1-oxotetrahydrothiopyranyl. A suitablevalue for such a group which bears 1 or 2 oxo or thioxo substituents is,for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl,2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl,2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl.

Q¹ is piperidinyl, which group is linked to the oxygen in Formula I by aring carbon atom.

A suitable value for a ‘Q’ group when it is heterocyclyl-(1-6C)alkyl is,for example, heterocyclylmethyl, 2-heterocyclylethyl and3-heterocyclylpropyl. The invention comprises corresponding suitablevalues for ‘Q’ groups when, for example, rather than aheterocyclyl-(1-6C)alkyl group, an (3-7C)cycloalkyl-(1-6C)alkyl or(3-7C)cycloalkenyl-(1-6C)alkyl is present.

Suitable values for any of the ‘R’ groups (R¹ to R¹⁹), W, or for variousgroups within a X¹, X² or Z group include:—

for halogeno fluoro, chloro, bromo and iodo; for (1-6C)alkyl: methyl,ethyl, propyl, isopropyl and tert-butyl; for (2-8C)alkenyl: vinyl,isopropenyl, allyl and but-2-enyl; for (2-8C)alkynyl: ethynyl,2-propynyl and but-2-ynyl; for (1-6C)alkoxy: methoxy, ethoxy, propoxy,isopropoxy and butoxy; for (2-6C)alkenyloxy: vinyloxy and allyloxy; for(2-6C)alkynyloxy: ethynyloxy and 2-propynyloxy; for (1-6C)alkylthio:methylthio, ethylthio and propylthio; for (1-6C)alkylsulfinyl:methylsulfinyl and ethylsulfinyl; for (1-6C)alkylsulfonyl:methylsulfonyl and ethylsulfonyl; for (1-6C)alkylamino: methylamino,ethylamino, propylamino, isopropylamino and butylamino; fordi-[(1-6C)alkyl]amino: dimethylamino, diethylamino, N-ethyl-N-methylamino and diisopropylamino; for (1-6C)alkoxycarbonyl:methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl andtert-butoxycarbonyl; for N-(1-6C)alkylcarbamoyl: N-methylcarbamoyl,N-ethylcarbamoyl and N-propylcarbamoyl; forN,N-di-[(1-6C)alkyl]carbamoyl: N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl and N,N-diethylcarbamoyl; for (2-6C)alkanoyl: acetyl,propionyl, butyryl and isobuyryl; for (2-6C)alkanoyloxy: acetoxy andpropionyloxy; for (2-6C)alkanoylamino: acetamido and propionamido; forN-(1-6C)alkyl-(2-6C)alkanoylamino: N-methylacetamido andN-methylpropionamido; for N-(1-6C)alkylsulfamoyl: N-methylsulfamoyl andN-ethylsulfamoyl; for N,N-di-[(1-6C)alkyl]sulfamoyl:N,N-dimethylsulfamoyl; for (1-6C)alkanesulfonylamino:methanesulfonylamino and ethanesulfonylamino; forN-(1-6C)alkyl-(1-6C)alkanesulfonylamino: N-methylmethanesulfonylaminoand N-methylethanesulfonylamino; for (3-6C)alkenoylamino: acrylamido,methacrylamido and crotonamido; for N-(1-6C)alkyl-(3-6C)alkenoylamino:N-methylacrylamido and N-methylcrotonamido; for (3-6C)alkynoylamino:propiolamido; for N-(1-6C)alkyl-(3-6C)alkynoylamino:N-methylpropiolamido; for amino-(1-6C)alkyl: aminomethyl, 2-aminoethyl,1-aminoethyl and 3-aminopropyl; for (1-6C)alkylamino-(1-6C)alkyl:methylaminomethyl, ethylaminomethyl, 1-methylaminoethyl,2-methylaminoethyl, 2-ethylaminoethyl and 3-methylaminopropyl; fordi-[(1-6C)alkyl]amino-(1-6C)alkyl: dimethylaminomethyl,diethylaminomethyl, 1-dimethylaminoethyl, 2-dimethylaminoethyl and3-dimethylaminopropyl; for halogeno-(1-6C)alkyl: chloromethyl,2-chloroethyl, 1-chloroethyl and 3-chloropropyl; forhydroxy-(1-6C)alkyl: hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl and3-hydroxypropyl; for (1-6C)alkoxy-(1-6C)alkyl: methoxymethyl,ethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl and3-methoxypropyl; for cyano-(1-6C)alkyl: cyanomethyl, 2-cyanoethyl,1-cyanoethyl and 3-cyanopropyl; for (1-6C)alkylthio-(1-6C)alkyl:methylthiomethyl, ethylthiomethyl, 2-methylthioethyl, 1-methylthioethyland 3-methylthiopropyl; for (1-6C)alkylsulfinyl-(1-6C)alkyl:methylsulfinylmethyl, ethylsulfinylmethyl, 2-methylsulfinylethyl,1-methylsulfinylethyl and 3-methylsulfinylpropyl; for(1-6C)alkylsulfonyl-(1-6C)alkyl: methylsulfonylmethyl,ethylsulfonylmethyl, 2-methylsulfonylethyl, 1-methylsulfonylethyl and3-methylsulfonylpropyl; for (2-6C)alkanoylamino-(1-6C)alkyl:acetamidomethyl, propionamidomethyl and 2-acetamidoethyl; forN-(1-6C)alkyl-(2-6C)alkanoylamino-(1-6C)alkyl: N-methylacetamidomethyl,2- (N-methylacetamido)ethyl and 2- (N-methylpropionamido)ethyl; for(1-6C)alkoxycarbonylamino-(1-6C)alkyl: methoxycarbonylaminomethyl,ethoxycarbonylaminomethyl, tert-butoxycarbonylaminomethyl and2-methoxycarbonylaminoethyl; (2-6C)alkanoyloxy-(1-6C)alkyl:acetoxymethyl, 2-acetoxyethyl and 2- propionyloxyethyl; forcarbamoyl-(1-6C)alkyl: carbamoylmethyl, 1-carbamoylethyl,2-carbamoylethyl and 3-carbamoylpropyl; for (2-6C)alkanoyl-(1-6C)alkyl:acetylmethyl and 2-acetylethyl; for N-(1-6C)alkylcarbamoyl-(1-6C)alkyl:N-methylcarbamoylmethyl, N-ethylcarbamoylmethyl,N-propylcarbamoylmethyl, 1-(N-methylcarbamoyl)ethyl,1-(N-ethylcarbamoyl)ethyl, 2-(N-methylcarbamoyl)ethyl,2-(N-ethylcarbamoyl)ethyl and 3-(N-methylcarbamoyl)propyl; forN,N-di[(1-6C)alkyl]carbamoyl-(1-6C)alkyl: N,N-dimethylcarbamoylmethyl,N,N-diethylcarbamoylmethyl, 2-(N,N-dimethylcarbamoyl)ethyl, and3-(N,N-dimethylcarbamoyl)propyl; for sulfamoyl(1-6C)alkyl:sulfamoylmethyl, 1-sulfamoylethyl, 2-sulfamoylethyl and3-sulfamoylpropyl; for N-(1-6C)alkylsulfamoyl(1-6C)alkyl:N-methylsulfamoylmethyl, N-ethylsulfamoylmethyl,N-propylsulfamoylmethyl, 1-(N-methylsulfamoyl)ethyl,2-(N-methylsulfamoyl)ethyl and 3-(N-methylsulfamoyl)propyl; and for N,Ndi-(1-6C)alkylsulfamoyl(1-6C)alkyl: N,N-dimethylsulfamoylmethyl,N,N-diethylsulfamoylmethyl, N methyl,N-ethylsulfamoylmethyl, 1-(N,N-dimethylsulfamoyl)ethyl, 1-(N,N-diethylsulfamoyl)ethyl,2-(N,N-dimethylsulfamoyl)ethyl, 2-(N,N-diethylsulfamoyl)ethyl and3-(N,N-dimethylsulfamoyl)propyl.

When, as defined hereinbefore Z in Formula I is a group of the formulaQ⁶-X⁹—, and X⁹ is SO₂N(R¹⁶), the SO₂ group is attached to Q⁶ and thenitrogen atom is attached to X² in Formula I. The same convention isapplied to other groups defined herein. For example when X² is a groupof the formula Q⁵-(CR¹⁴R¹⁵)_(p), the Q⁵ group is attached to the group Zin Formula I and the (CR¹⁴R¹⁵)_(p) group is attached to the X¹ group inFormula I.

As defined hereinbefore, adjacent carbon atoms in any (2-6C)alkylenechain within, for example, a R¹ substituent may be optionally separatedby the insertion into the chain of a group such as O, CON(R³), N(R³) orC≡C. For example, insertion of a C≡C group into the ethylene chainwithin a 2-morpholinoethoxy group gives rise to a4-morpholinobut-2-ynyloxy group and, for example, insertion of a CONHgroup into the ethylene chain within a 3-methoxypropoxy group gives riseto, for example, a 2-(2-methoxyacetamido)ethoxy group. It is to beunderstood that the term (2-6C)alkylene chain refers to any CH₂CH₂ group(for example within R¹) and includes, for example alkylene chains withina (1-6C)alkyl, (1-6C)alkoxy, (2-8C)alkenyl, (2-8C)alkenyloxy,(2-8C)alkynyl and (2-8C)alkynyloxy group. For example the insertion of aN(CH₃) group between the third and fourth carbon atoms in ahex-5-enyloxy group in R¹ gives rise to a3-(N-methyl-N-allylamino)propoxy group.

When, as defined hereinbefore, any CH₂═CH— or HC≡C— group within a R¹substituent optionally bears at the terminal CH₂═ or HC≡ position asubstituent such as a group of the formula Q³-X⁴- wherein X⁴ is, forexample, NHCO and Q³ is a heterocyclyl-(1-6C)alkyl group, suitable R¹substituents so formed include, for example,N-[heterocyclyl-(1-6C)alkyl]carbamoylvinyl groups such asN-(2-pyrrolidin-1-ylethyl)carbamoylvinyl orN—[heterocyclyl-(1-6C)alkyl]carbamoylethynyl groups such asN-(2-pyrrolidin-1-ylethyl)carbamoylethynyl.

When reference is made herein to a CH₂ or CH₃ group optionally bearingon each said CH₂ or CH₃ group one or more halogeno or (1-6C)alkylsubstituents, there are suitably 1 or 2 halogeno or (1-6C)alkylsubstituents present on each said CH₂ group and there are suitably 1, 2or 3 such substituents present on each said CH₃ group.

Where reference is made herein to any CH₂ or CH₃ group optionallybearing on each said CH₂ or CH₃ group a substituent as defined herein,suitable substituents so formed include, for example,hydroxy-substituted heterocyclyl-(1-6C)alkoxy groups such as2-hydroxy-3-piperidinopropoxy and 2-hydroxy-3-morpholinopropoxy,hydroxy-substituted heterocyclyl-(1-6C)alkylamino groups such as2-hydroxy-3-piperidinopropylamino and 2-hydroxy-3-morpholinopropylamino,and hydroxy-substituted (2-6)alkanoyl groups such as hydroxyacetyl,2-hydroxypropionyl and 2-hydroxybutyryl.

Where reference is made herein to “any CH₂ or CH₃ group, other than aCH₂ group within a heterocyclyl group, optionally bearing asubstituent”, it is to be understood that such a statement is presentonly to distinguish between optional substituents that may be presenton, for example, a CH₃ group in an alkyl group from substituents thatmay be present on carbon atoms of a heterocyclyl group. Accordingly, itis to be understood, that this statement does not exclude othersubstituents being present on ring carbon atoms in a heterocyclyl groupwhen it is stated herein that said heterocyclyl group may alsooptionally bear one or more substituents. For example, if R¹ is3-(pyrrolidin-1-yl)propoxy and herein it is stated that a CH₂ or CH₃group within, for example, a R¹ substituent, other than a CH₂ groupwithin a heterocyclyl group, optionally bears a hydroxy substituent, andthat any heterocyclyl group within R¹ optionally bears an alkylsubstituent, then the optional hydroxy substituent may be present on aCH₂ of the propoxy group to give for example a2-hydroxy-3-(pyrrolidin-1-yl)propoxy group. Similarly an alkyl groupsuch as methyl may be present on the pyrrolidinyl ring to give, forexample, a 3-(3-methylpyrrolidin-1-yl)propoxy group. Equally, thepropoxy group may be substituted by a hydroxy group and the pyrrolidinylring may be substituted by a methyl group to give, for example, a2-hydroxy-3-(3-methylpyrrolidin-1-yl)propoxy group.

For the avoidance of doubt, when W is oxo, a CH₂ in Q¹ is substituted byO to give a C(O) group.

It is to be understood that reference herein to Q¹ being, for examplepiperidin-4-yl refers to the attachment of the piperidine ring to theoxygen in Formula I. The piperidine ring is further substituted at the1-position by the group Z-X²-X²- and optionally bears one or more Wsubstituents on one or more of the available piperidinyl ring carbonatoms.

It is to be understood that certain compounds of the Formula I may existin solvated as well as unsolvated forms such as, for example, hydratedforms. It is to be understood that the invention encompasses all suchsolvated forms which exhibit an inhibitory effect on an erbB receptortyrosine kinase.

It is also to be understood that certain compounds of the Formula I mayexhibit polymorphism, and that the invention encompasses all such formswhich exhibit an inhibitory effect on an erbB receptor tyrosine kinase.

It is also to be understood that the invention relates to all tautomericforms of the compounds of the Formula I forms which exhibit aninhibitory effect on an erbB receptor tyrosine kinase.

A suitable pharmaceutically acceptable salt of a compound of the FormulaI is, for example, an acid-addition salt of a compound of the Formula I,for example an acid-addition salt with an inorganic or organic acid suchas hydrochloric, hydrobromic, sulfuric, trifluoroacetic, citric ormaleic acid; or, for example, a salt of a compound of the Formula Iwhich is sufficiently acidic, for example an alkali or alkaline earthmetal salt such as a calcium or magnesium salt, or an ammonium salt, ora salt with an organic base such as methylamine, dimethylamine,trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

The term “pharmaceutically acceptable ester” used herein refers to anester of a quinazoline derivative of the Formula I which hydrolyses invivo to leave the parent compound or a pharmaceutically acceptable saltthereof. An in-vivo hydrolysable ester of a quinazoline of Formula I maybe used to alter or improve the physical and/or pharmacokinetic profileof the parent compound, for example the solubility. Suitable estergroups that may be used in the formation of pharmaceutically acceptableester prodrugs are well known, for example as discussed in for example:

Pro-drugs as Novel Delivery Systems, T. Higuchi and V. Stella, Vol. 14of the ACS Symposium Series, and in Edward B. Roche, ed.; BioreversibleCarriers in Drug Design, American Pharmaceutical Association andPergamon Press, 1987;

Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methodsin Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al.(Academic Press, 1985);A Textbook of Drug Design and Development, edited by Krogsgaard-Larsenand H. Bundgaard, Chapter 5 “Design and Application of Prodrugs”, by H.Bundgaard p. 113-191 (1991);

H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); H.Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988);and N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).

A particular pharmaceutically acceptable ester of a quinazolinederivative of the Formula I or a pharmaceutically acceptable saltthereof is, an ester formed with a carboxy or, particularly, a hydroxygroup (for example when Z is hydroxy) in Formula I, which ester ishydrolysed in the human or animal body to produce the parent quinazolineof Formula I when administered to a warm blooded animal such as a human.

Suitable pharmaceutically acceptable esters for a carboxy group inFormula I include C₁₋₆alkoxymethyl esters for example methoxymethyl,C₁₋₆alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidylesters, C₃₋₈cycloalkoxycarbonyloxyC₁₋₆alkyl esters for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters forexample 5-methyl-1,3-dioxolen-2-onylmethyl; andC₁₋₆alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyland may be formed at any carboxy group in the compounds of thisinvention.

Suitable pharmaceutically acceptable esters for a hydroxy group inFormula I or a pharmaceutically acceptable salt thereof includeinorganic esters such as phosphate esters, α-acyloxyalkyl ethers andrelated compounds, and esters derived from pharmaceutically acceptablealiphatic carboxylic acids, particularly alkanoic, alkenoic,cycloalkanoic and alkanedioic acids, in which each alkyl or alkenylmoiety advantageously has not more than 6 carbon atoms, and may beformed at any hydroxy group in the compounds of this invention, forexample when Z is hydroxy or contains a hydroxy group. Followingadministration, the pharmaceutically acceptable ester undergoes in-vivohydrolysis breakdown to give the parent carboxy/hydroxy group in thequinazoline derivative of Formula I.

Examples of α-acyloxyalkyl ethers that may be used to form apharmaceutically acceptable ester include acetoxymethoxy and2,2-dimethylpropionyloxymethoxy. A selection of pharmaceuticallyacceptable ester forming groups for a hydroxy group in Formula I (forexample when Z is hydroxy) include (1-6C)alkanoyl, benzoyl, phenylacetyland substituted benzoyl and phenylacetyl, (1-6C)alkoxycarbonyl (to givealkyl carbonate esters), di-(1-4C)alkylcarbamoyl andN-(di-(1-4C)alkylaminoethyl)-N-(1-4C)alkylcarbamoyl (to givecarbamates), di-(1-4C)alkylaminoacetyl and carboxyacetyl. Examples ofsubstituents on benzoyl include chloromethyl or aminomethyl,(1-4C)alkylaminomethyl and di-((1-4C)alkyl)aminomethyl, and morpholinoor piperazino linked from a ring nitrogen atom via a methylene linkinggroup to the 3- or 4-position of the benzoyl ring.

Particular pharmaceutically acceptable esters are phosphate estersformed with a hydroxy group in the quinazoline derivative for theFormula I (for example when Z is hydroxy or contains a hydroxy group),or a pharmaceutically acceptable salt thereof. More particularly,pharmaceutically acceptable esters include quinazoline derivatives ofthe Formula I in which a hydroxy group in Formula I forms a phosphoryl(npd is 1) or phosphiryl (npd is 0) ester of the formula (PD1), or apharmaceutically acceptable salt thereof:

Another particular pharmaceutically acceptable ester is a quinazolinederivative of the Formula I in which a hydroxy in Formula I (for examplewhen Z is hydroxy) forms a phosphoryl to give a group of the formula(PD1) wherein npd is 1.

Useful intermediates for the preparation of such esters includecompounds containing a group of formula (PD1) in which either or both ofthe —OH groups in (PD1) is independently protected by (1-4C)alkyl (suchcompounds also being interesting compounds in their own right), phenylor phenyl-(1-4C)alkyl (such phenyl groups being optionally substitutedby 1 or 2 groups independently selected from (1-4C)alkyl, nitro, haloand (1-4C)alkoxy).

Pharmaceutically acceptable esters of a quinazoline derivative ofFormula I containing a group such as (PD1), may be prepared by reactionof a quinazoline derivative Formula I with a suitably protectedphosphorylating agent (for example, containing a chloro or dialkylaminoleaving group), followed by oxidation (if necessary) and deprotection.Suitable phosphorylating agents are well known and include, for exampleprotected phosphoramidite compounds such as aN,N-di-[(1-6C)alkyl]-phosphoramidite, for example di-tert-butylN,N-diethylphosphoramidite.

It is to be understood that an ester group in the quinazoline derivativeof the Formula I may form a pharmaceutically acceptable salt of theester group and that such salts form part of the present invention.Where pharmaceutically acceptable salts of a pharmaceutically acceptableester is required this is achieved by conventional techniques well knownto those of ordinary skill in the art. Thus, for example, compoundscontaining a group of formula (PD1), may ionise (partially or fully) toform salts with an appropriate number of counter-ions. By way ofexample, if a pharmaceutically acceptable ester pro-drug of aquinazoline derivative Formula I contains a (PD1) group, there are twoHO-P- functionalities present, each of which may form an appropriatesalt with a suitable counter-ion. Suitable salts of a group of theformula (PD1) are base salts such as an alkali metal salt for examplesodium, an alkaline earth metal salt for example calcium or magnesium oran organic amine salt for example triethylamine, ortris-(2-hydroxyethyl)amine. Thus for example the group (PD1) may form, amono- or di-sodium salt).

Particular novel compounds of the invention include, for example,quinazoline derivatives of the Formula I, or pharmaceutically acceptablesalts, or pharmaceutically acceptable esters thereof, wherein, unlessotherwise stated, each of R¹, R², W, Q¹, X¹, X², a, b and Z has any ofthe meanings defined hereinbefore or in paragraphs (a) to (nnnn)hereinafter:—

(a) R¹ is selected from hydrogen, hydroxy, (1-6C)alkoxy,(2-6C)alkenyloxy, (2-6C)alkynyloxy, or from a group of the formula:

Q²-X³-

wherein X³ is a direct bond or is O, and Q² is (3-7C)cycloalkyl,(3-7C)cycloalkyl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl,and wherein adjacent carbon atoms in any (2-6C)alkylene chain within aR¹ substituent are optionally separated by the insertion into the chainof a group selected from O, N(R³), CON(R³), N(R³)CO, CH═CH and C≡Cwherein R³ is hydrogen or (1-6C)alkyl,

and wherein any CH₂═CH— or HC≡C— group within a R³ substituentoptionally bears at the terminal CH₂═ or HC≡ position a substituentselected from carbamoyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, amino-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl orfrom a group of the formula:

Q³-X⁴-

wherein X⁴ is a direct bond or is selected from CO and N(R⁴)CO, whereinR⁴ is hydrogen or (1-6C)alkyl, and Q³ is heterocyclyl orheterocyclyl-(1-6C)alkyl,

and wherein any CH₂ or CH₃ group within a R¹ substituent, other than aCH₂ group within a heterocyclyl ring, optionally bears on each said CH₂or CH₃ group one or more halogeno or (1-6C)alkyl substituents or asubstituent selected from hydroxy, amino, cyano, carbamoyl,(1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,N-(1-6C)alkylcarbamoyl and N,N-di-[(1-6C)alkyl]carbamoyl, or from agroup of the formula:

-X⁵-Q⁴

wherein X⁵ is a direct bond or is selected from O, N(R⁵), CON(R⁵),N(R⁵)CO and C(R⁵)₂O, wherein R⁵ is hydrogen or (1-6C)alkyl, and Q⁴ isheterocyclyl or heterocyclyl-(1-6C)alkyl,

and wherein any heterocyclyl group within a substituent on R¹ optionallybears 1, 2 or 3 substituents, which may be the same or different,selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino,carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy,(1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,or from a group of the formula:

-X⁶-R⁶

wherein X⁶ is a direct bond or is selected from O and N(R⁷), wherein R⁷is hydrogen or (1-6C)alkyl, and R⁶ is halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,di-[(1-6C)alkyl]amino-(1-6C)alkyl, carbamoyl-(1-6C)alkyl,N-(1-6C)alkylcarbamoyl-(1-6C)alkyl andN,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl, and wherein any heterocyclylgroup within a substituent on R¹ optionally bears 1 or 2 oxosubstituents;(b) R¹ is selected from hydrogen, hydroxy, (1-6C)alkoxy,(2-6C)alkenyloxy, (2-6C)alkynyloxy, or from a group of the formula:

Q²-X³-

wherein X³ is a direct bond or is O, and Q² is heterocyclyl orheterocyclyl-(1-6C)alkyl,

and wherein adjacent carbon atoms in any (2-6C)alkylene chain within aR¹ substituent are optionally separated by the insertion into the chainof a group selected from O, N(R³), CON(R³), N(R³)CO, CH═CH and C≡Cwherein R³ is hydrogen or (1-6C)alkyl, and wherein any CH₂═CH— or HC≡C—group within a R¹ substituent optionally bears at the terminal CH₂═ orHC≡ position a substituent selected from carbamoyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl anddi-[(1-6C)alkyl]amino-(1-6C)alkyl

and wherein any CH₂ or CH₃ group within a R¹ substituent, other than aCH₂ group within a heterocyclyl ring, optionally bears on each said CH₂or CH₃ group one or more halogeno or (1-6C)alkyl substituents or asubstituent selected from hydroxy, amino, cyano, carbamoyl,(1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,N-(1-6C)alkylcarbamoyl and N,N-di-[(1-6C)alkyl]carbamoyl, or from agroup of the formula:

-X⁵-Q⁴

wherein X⁵ is a direct bond or is selected from O, N(R⁵), CON(R⁵),N(R⁵)CO and C(R⁵)₂O, wherein R⁵ is hydrogen or (1-6C)alkyl, and Q⁴ isheterocyclyl or heterocyclyl-(1-6C)alkyl,

and wherein any heterocyclyl group within a substituent on R¹ optionallybears 1, 2 or 3 substituents, which may be the same or different,selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl,(1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkylsulfonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, or from a group of theformula:

-X⁶-R⁶

wherein X⁶ is a direct bond or is selected from O and N(R⁷), wherein R⁷is hydrogen or (1-6C)alkyl, and R⁶ is halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl anddi-[(1-6C)alkyl]amino-(1-6C)alkyl, and wherein any heterocyclyl groupwithin a substituent on R¹ optionally bears 1 or 2 oxo substituents;(c) R¹ is selected from hydrogen, hydroxy, (1-6C)alkoxy,(2-6C)alkenyloxy and (2-6C)alkynyloxy,

and wherein adjacent carbon atoms in any (2-6C)alkylene chain within aR¹ substituent are optionally separated by the insertion into the chainof a group selected from O, N(R³), CON(R³), N(R³)CO, CH═CH and C≡Cwherein R³ is hydrogen or (1-6C)alkyl,

and wherein any CH₂ or CH₃ group within a R¹ substituent, other than aCH₂ group within a heterocyclyl ring, optionally bears on each said CH₂or CH₃ group one or more halogeno or (1-6C)alkyl substituents or asubstituent selected from hydroxy, amino, cyano, carbamoyl,(1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,N-(1-6C)alkylcarbamoyl and N,N-di-[(1-6C)alkyl]carbamoyl;

(d) R¹ is selected from hydrogen, hydroxy, (1-6C)alkoxy, or from a groupof the formula:

Q²-X³

wherein X³ is O, and Q² is (3-7C)cycloalkyl,(3-7C)cycloalkyl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl,

and wherein adjacent carbon atoms in any (2-6C)alkylene chain within aR¹ substituent are optionally separated by the insertion into the chainof a group selected from O and N(R³), wherein R³ is hydrogen or(1-4C)alkyl,

and wherein any CH₂ or CH₃ group within a R¹ substituent, other than aCH₂ group within a heterocyclyl ring, optionally bears on each said CH₂or CH₃ group one or more halogeno or (1-6C)alkyl substituents or asubstituent selected from hydroxy, amino, cyano, (1-6C)alkoxy,(1-6C)alkylamino and di-[(1-6C)alkyl]amino, and wherein any heterocyclylgroup within a substituent on R¹ optionally bears 1, 2 or 3substituents, which may be the same or different, selected fromhalogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carbamoyl,(1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy,(1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl and(2-6C)alkanoyl,

and wherein any heterocyclyl group within a substituent on R¹ optionallybears 1 or 2 oxo substituents;

(e) R¹ is selected from hydrogen, hydroxy, (1-6C)alkoxy, or from a groupof the formula:

Q²-X³-

wherein X³ is O, and Q² is azetidin-3-yl-(1-4C)alkyl,azetidin-1-yl-(2-4C)alkyl, pyrrolidin-2-yl-(1-4C)alkyl,pyrrolidin-3-yl-(1-4C)alkyl, pyrrolidin-1-yl-(2-4C)alkyl,piperidin-2-yl-(1-4C)alkyl, piperidin-3-yl-(1-4C)alkyl,piperidin-4-yl-(1-4C)alkyl, piperidino-(2-4C)alkyl,piperazino-(2-4C)alkyl or morpholino-(2-4C)alkyl,

and wherein adjacent carbon atoms in any (2-6C)alkylene chain within aR¹ substituent are optionally separated by the insertion into the chainof a group selected from O and N(R³), wherein R³ is hydrogen or(1-4C)alkyl,

and wherein any CH₂ or CH₃ group within a R¹ substituent, other than aCH₂ group within a heterocyclyl ring, optionally bears on each said CH₂or CH₃ group one or more halogeno or (1-6C)alkyl substituents or asubstituent selected from hydroxy, (1-4C)alkoxy, amino, (1-4C)alkylaminoand di-[(1-4C)alkyl]amino,

and wherein any heterocyclyl group within a substituent on R¹ optionallybears 1, 2 or 3 substituents, which may be the same or different,selected from halogeno, hydroxy, amino, carbamoyl, (1-4C)alkyl,(2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, (1-4C)alkylsulfonyl,(1-4C)alkylamino, di-[(1-4C)alkyl]amino, N-(1-4C)alkylcarbamoyl,N,N-di-(1-4C)alkyl]carbamoyl and (2-4C)alkanoyl,

and wherein any heterocyclyl group within a substituent on R¹ optionallybears 1 oxo substituent (preferably any oxo group on a morpholino groupin R¹ is located at the 3 or 5 position on the morpholino ring);

(f) R¹ is selected from hydrogen, hydroxy, (1-4C)alkoxy,hydroxy-(2-4C)alkoxy, (1-3C)alkoxy-(2-4C)alkoxy or from a group of theformula:

Q²-X³-

wherein X³ is O, and Q² is azetidin-1-yl-(2-4C)alkyl,pyrrolidin-1-yl-(2-4C)alkyl, piperidino-(2-4C)alkyl,piperazino-(2-4C)alkyl or morpholino-(2-4C)alkyl,

and wherein any heterocyclyl group within a substituent on R¹ optionallybears 1, 2 or 3 substituents, which may be the same or different,selected from halogeno, hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy,(1-4C)alkylsulfonyl, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, and(2-4C)alkanoyl,

and wherein any heterocyclyl group within a substituent on R¹ optionallybears 1 oxo substituent;

(g) R¹ is selected from hydrogen, hydroxy, methoxy, ethoxy, propoxy,isopropyloxy, 2-hydroxyethoxy, 2-fluoroethoxy, cyclopropylmethoxy,2-cyclopropylethoxy, vinyloxy, allyloxy, ethynyloxy, 2-propynyloxy,tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,tetrahydropyran-4-yloxy, tetrahydrofurfuryloxy,tetrahydrofuran-3-ylmethoxy, 2-(tetrahydrofuran-2-yl)ethoxy,3-(tetrahydrofuran-2-yl)propoxy, 2-(tetrahydrofuran-3-yl)ethoxy,3-(tetrahydrofuran-3-yl)propoxy, tetrahydropyranylmethoxy,2-tetrahydropyranylethoxy, 3-tetrahydropyranylpropoxy,2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, pyrrolidin-3-yloxy,pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy,3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy,2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, piperidin-3-yloxy, piperidin-4-yloxy,piperidin-3-ylmethoxy, 2-piperidin-3-ylethoxy, piperidin-4-ylmethoxy,2-piperidin-4-ylethoxy, 2-homopiperidin-1-ylethoxy,3-homopiperidin-1-ylpropoxy, 2-piperazin-1-ylethoxy,3-piperazin-1-ylpropoxy, 2-homopiperazin-1-ylethoxy,3-homopiperazin-1-ylpropoxy, pyrrolidin-1-yl, morpholino, piperidino andpiperazin-1-yl,

and wherein adjacent carbon atoms in any (2-6C)alkylene chain within aR¹ substituent are optionally separated by the insertion into the chainof a group selected from O, NH, N(CH₃), CH═CH and C≡C,

and when R¹ is a vinyloxy, allyloxy, ethynyloxy or 2-propynyloxy group,the R¹ substituent optionally bears at the terminal CH₂═ or HC≡ positiona substituent selected from N-(2-dimethylaminoethyl)carbamoyl,N-(3-dimethylaminopropyl)carbamoyl, methylaminomethyl,2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl,dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl and4-dimethylaminobutyl, or from a group of the formula:

Q³-X⁴-

wherein X⁴ is a direct bond or is NHCO or N(CH₃)CO and Q³ ispyrrolidin-1-ylmethyl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl,4-pyrrolidin-1-ylbutyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl,3-pyrrolidin-2-ylpropyl, morpholinomethyl, 2-morpholinoethyl,3-morpholinopropyl, 4-morpholinobutyl, piperidinomethyl,2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl,piperidin-3-ylmethyl, 2-piperidin-3-ylethyl, piperidin-4-ylmethyl,2-piperidin-4-ylethyl, piperazin-1-ylmethyl, 2-piperazin-1-ylethyl,3-piperazin-1-ylpropyl or 4-piperazin-1-ylbutyl,

and wherein any CH₂ group which is attached to 2 carbon atoms (otherthan a CH₂ group within a heterocyclyl ring) or any CH₃ group which isattached to a carbon atom within a R¹ substituent optionally bears oneach said CH₂ or CH₃ group a substituent selected from hydroxy, amino,methoxy, ethoxy, methylsulfonyl, methylamino and dimethylamino,

and wherein any heterocyclyl group within a substituent on R¹ optionallybears 1 or 2 substituents, which may be the same or different, selectedfrom fluoro, chloro, trifluoromethyl, hydroxy, amino, methylamino,ethylamino, dimethylamino, diethylamino, carbamoyl, methyl, ethyl,n-propyl, isopropyl and methoxy, and any piperidin-3-ylmethyl,piperidin-4-ylmethyl or piperazin-1-yl group within a R¹ substituent isoptionally N-substituted with 2-methoxyethyl, 3-methoxypropyl,2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-methylaminopropyl,2-dimethylaminoethyl, 3-dimethylaminopropyl, acetyl or propionyl,

and wherein any heterocyclyl group within a substituent on R¹ optionallybears 1 or 2 oxo substituents;

(h) R¹ is selected from hydrogen, hydroxy, (1-6C)alkoxy,(3-7C)cycloalkyl-oxy and (3-7C)cycloalkyl-(1-6C)alkoxy,

and wherein any CH₂ or CH₃ group within a R¹ substituent optionallybears on each said CH₂ or CH₃ group one or more halogeno or (1-6C)alkylsubstituents, or a substituent selected from hydroxy, cyano, amino,carboxy, carbamoyl, sulfamoyl, oxo, (1-6C)alkoxy, (1-6C)alkylthio,(1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, N-(1-6C)alkylsulfamoyl andN,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino andN-(1-6C)alkyl-(1-6C)alkanesulfonylamino;

(i) R¹ is selected from hydrogen, hydroxy, (1-6C)alkoxy,(3-7C)cycloalkyl-oxy and (3-7C)cycloalkyl-(1-6C)alkoxy,

and wherein any CH₂ or CH₃ group within a R¹ substituent optionallybears on each said CH₂ or CH₃ group one or more fluoro or chlorosubstituents, or a substituent selected from hydroxy, amino,(1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]amino;

(j) R¹ is selected from hydrogen, hydroxy, (1-6C)alkoxy,(3-7C)cycloalkyl-oxy and (3-7C)cycloalkyl-(1-6C)alkoxy,

and wherein adjacent carbon atoms in any (2-6C)alkylene chain within aR¹ substituent are optionally separated by the insertion into the chainof an O atom,

and wherein any CH₂ or CH₃ group within a R¹ substituent optionallybears on each said CH₂ or CH₃ group one or more fluoro or chlorosubstituents, or a substituent selected from hydroxy and (1-4C)alkoxy;

(k) R¹ is selected from hydrogen, (1-6C)alkoxy,cyclopropyl-(1-4C)alkoxy, cyclobutyl-(1-4C)alkoxy,cyclopentyl-(1-4C)alkoxy, cyclohexyl-(1-6C)alkoxy,tetrahydrofuranyl-(1-4C)alkoxy and tetrahydropyranyl-(1-4C)alkoxy,

and wherein adjacent carbon atoms in any (2-6C)alkylene chain within aR¹ substituent are optionally separated by the insertion into the chainof an O atom,

and wherein any CH₂ or CH₃ group within a R¹ substituent optionallybears on each said CH₂ or CH₃ group one or more fluoro or chlorosubstituents, or a substituent selected from hydroxy and (1-3C)alkoxy;

(l) R¹ is selected from hydrogen, (1-6C)alkoxy, cyclopropylmethoxy and2-cyclopropylethoxy,

and wherein any CH₂ or CH₃ group within a R¹ substituent optionallybears on each said CH₂ or CH₃ group one or more fluoro or chlorosubstituents, or a substituent selected from hydroxy, methoxy andethoxy;

(m) R¹ is selected from methoxy, ethoxy, propyloxy, isopropyloxy,cyclopropylmethoxy, 2-hydroxyethoxy, 2-fluoroethoxy, 2-methoxyethoxy,2-ethoxyethoxy, 2,2-difluoroethoxy 2,2,2-trifluoroethoxy,2-(pyrrolidin-1-yl)ethoxy, 3-(pyrrolidin-1-yl)propoxy,2-piperidinoethoxy, 3-piperidinopropyl, 2-piperazinoethoxy,3-piperazinopropoxy, 2-morpholinoethoxy and 3-morpholinopropoxy;(n) R¹ is selected from hydrogen methoxy, ethoxy, propyloxy,isopropyloxy, cyclopropylmethoxy, 2-hydroxyethoxy, 2-fluoroethoxy,2-methoxyethoxy, 2-ethoxyethoxy, 2,2-difluoroethoxy and2,2,2-trifluoroethoxy;(o) R¹ is selected from (1-4C)alkoxy, hydroxy-(2-4C)alkoxy and(1-3C)alkoxy-(2-3C)alkoxy;(p) R¹ is selected from hydrogen and (1-3C)alkoxy (particularly R¹ is(1-3C)alkoxy such as methoxy, ethoxy and isopropyloxy);(q) R¹ is hydrogen;(r) R¹ is methoxy;(s) each R², which may be the same or different, is selected fromhalogeno, cyano, nitro, hydroxy, amino, carboxy, (1-6C)alkyl,(2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy, and a group ofthe formula:

X⁷-R⁸

wherein X⁷ is a direct bond or is selected from O and N(R⁹), wherein R⁹is hydrogen or (1-6C)alkyl, and R⁵ is halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,di-[(1-6C)alkyl]amino-(1-6C)alkyl;(t) each R², which may be the same or different, is selected fromhalogeno, hydroxy, amino, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl,(1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino;(u) each R², which may be the same or different, is selected fromfluoro, chloro, bromo, iodo, cyano, hydroxy, trifluoromethyl,(1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl and (1-4C)alkoxy;(v) each R², which may be the same or different, is selected fromfluoro, chloro, bromo, (1-4C)alkyl, (2-4C)alkenyl and (2-4C)alkynyl;(w) each R², which may be the same or different, is selected fromfluoro, chloro, bromo, iodo, cyano, carbamoyl, hydroxy, trifluoromethyl,methyl, ethyl, isopropyl, methoxy, ethoxy, vinyl, allyl, ethynyl,1-propynyl, 2-propynyl, N-methylcarbamoyl, N-ethylcarbamoyl andN,N-dimethylcarbamoyl;(x) each R², which may be the same or different, is selected fromfluoro, chloro, bromo, iodo, cyano, hydroxy, trifluoromethyl, methyl,ethyl, isopropyl, methoxy, ethoxy, vinyl, allyl, ethynyl, 1-propynyl,and 2-propynyl;(y) each R², which may be the same or different, is selected fromfluoro, chloro, bromo, cyano, hydroxy, trifluoromethyl, methyl, ethyl,methoxy, ethoxy and ethynyl;(z) each R², which may be the same or different, is selected fromfluoro, chloro, bromo and ethynyl;(aa) each R², which may be the same or different, is selected fromhalogeno (particularly fluoro, chloro and bromo);(bb) b is 1, 2 or 3 and one R² is at the meta (3-) position on theanilino group in Formula 1;(cc) b is 1, 2 or 3 and each R², which may be the same or different, isas defined in any of (s) to (aa) above;(dd) b is 1, 2 or 3, one R² is at the meta (3-) position on the anilinogroup in Formula 1 and is halogeno, and when b is 2 or 3 the other R²group(s), which may be the same or different, are as defined in any ofany of (s) to (aa) above;(ee) b is 1, 2 or 3, each R², which may be the same or different, ishalogeno, and wherein one R² is at the meta (3-) position on the anilinogroup;(ff) b is 1 or 2, each R², which may be the same or different, ishalogeno (particularly fluoro, chloro or bromo) and wherein one R² is atthe meta (3-) position and the other R² is at the ortho (2-) or para(4-) position on the anilino group;(gg) b is 1 or 2, one R² is at the meta (3-) position on the anilinogroup and is chloro or bromo (particularly chloro), and when b is 2 theother R² group is selected from fluoro, chloro and bromo;(hh) the anilino group at the 4-position on the quinazoline ring inFormula I is selected from 3-chloro-4-fluoroanilino,3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino,2-fluoro-5-chloroanilino, 3-bromoanilino and 3-ethynylanilino;(ii) the anilino group at the 4-position on the quinazoline ring inFormula I is selected from 3-chloro-4-fluoroanilino,3-chloro-2-fluoroanilino, 2-fluoro-5-chloroanilino, 3-bromoanilino,3-methylanilino and 3-ethynylanilino;(jj) the anilino group at the 4-position on the quinazoline ring inFormula I is 3-chloro-4-fluoroanilino;(kk) the anilino group at the 4-position on the quinazoline ring inFormula I is 3-chloro-2-fluoroanilino or 3-bromo-2-fluoroanilino (moreparticularly the anilino is 3-chloro-2-fluoroanilino);(ll) Q¹ is selected from piperidin-3-yl and piperidin-4-yl;(mm) Q¹ is piperidin-4-yl;(nn) each W, which may be the same or different, is selected fromhalogeno, trifluoromethyl, hydroxy, oxo, (1-6C)alkyl, (1-6C)alkoxy, andfrom a group of the formula:

-X⁸-R¹⁰

wherein X⁸ is a direct bond or is O, and R¹⁰ is halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl or (1-6C)alkoxy-(1-6C)alkyl;

(oo) each W, which may be the same or different, is selected fromhalogeno, hydroxy, oxo, (1-6C)alkyl and (1-6C)alkoxy;(pp) each W, which may be the same or different, is selected fromhalogeno (particularly fluoro), hydroxy, (1-3C)alkyl and (1-3C)alkoxy;(qq) a is 0, 1, or 2 and each W, which may be the same or different, isas defined in any of (nn) to (pp);(rr) a is 0 or 1 and W is as defined in any of (nn) to (pp);(ss) a is 0;(tt) Q¹ is piperidin-4-yl, a is 0 or 1 and W is as defined in any of(nn) to (pp);

(uu) X¹ is CO; (vv) X¹ is SO₂;

(ww) X² is a group of the formula:

—(CR¹²R¹³)_(p)-(Q⁵)_(m)-(CR¹⁴R¹⁵)_(q)-

wherein m is 0 or 1, p is 0, 1, 2, 3 or 4 and q is 0, 1, 2, 3 or 4,

each of R¹², R¹³, R¹⁴ and R¹⁵, which may be the same or different, isselected from hydrogen, (1-6C)alkyl, amino, (1-6C)alkylamino anddi-[(1-6C)alkyl]amino, and Q⁵ is selected from (3-7C)cycloalkylene and(3-7C)cycloalkenylene,

and wherein any CH₂ or CH₃ group within an X² group, optionally bears oneach said CH₂ or CH₃ group one or more halogeno or (1-6C)alkylsubstituents,

and wherein any CH₂ group which is attached to 2 carbon atoms or any CH₃group which is attached to a carbon atom within a X² substituentoptionally bears on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy, cyano, amino, (1-6C)alkoxy, (1-6C)alkylamino anddi-[(1-6C)alkyl]amino;

(xx) X² is selected from a group of the formula -(Q⁵)_(m)-(CR¹⁴R¹⁵)_(q)—and a group of the formula —(CR¹²R¹³)_(q)-(Q⁵)_(m)-, wherein m is 0 or1, q is 1, 2, 3 or 4, and Q⁵, R¹², R¹³, R¹⁴ and R¹⁵ are as hereinbeforedefined;(yy) X² is a group of the formula -Q⁵-, for example (3-7C)cycloalkylenesuch as cyclopropylidene;(zz) X² is selected from cyclopropylene, cyclopbutylene, cyclopentylene,cyclohexylene, methylene-(3-6C)cycloalkylene,(3-6C)cycloalkylene-methylene-, ethylene-(3-6C)cycloalkylene and(3-6C)cycloalkylene-ethylene-,

and wherein and wherein any CH₂ or CH₃ group within X², optionally bearson each said CH₂ or CH₃ group one or more halogeno or (1-6C)alkylsubstituents or a substituent selected from hydroxy, amino,(1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino;

(aaa) X² is a group of the formula —(CR²R³)_(q)—,

q is 1, 2, 3 or 4 (particularly 1 or 2),

each of R¹² and R¹³, which may be the same or different, is selectedfrom hydrogen and (1-6C)alkyl,

and wherein and wherein any CH₂ or CH₃ group within X², optionally bearson each said CH₂ or CH₃ group one or more halogeno substituents,

and wherein any CH₂ group which is attached to 2 carbon atoms or any CH₃group which is attached to a carbon atom within a X² substituentoptionally bears on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylamino anddi-[(1-6C)alkyl]amino;

(bbb) X² is a group of the formula —(CR¹²R¹³)_(q)—,

q is 1, 2 or 3,

each of R¹² and R¹³, which may be the same or different, is selectedfrom hydrogen and (1-6C)alkyl,

and wherein any CH₂ or CH₃ group within an X² group, optionally bears oneach said CH₂ or CH₃ group one or more halogeno substituents,

and wherein any CH₂ group which is attached to 2 carbon atoms or any CH₃group which is attached to a carbon atom within a X² substituentoptionally bears on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy, and (1-6C)alkoxy;

(ccc) X² is a group of the formula —(CR¹²R¹³)_(q)—(CR^(2aa)R^(13aa))-,

q is 1, 2 or 3 (particularly 1 or 2, more particularly 1),

each of R², R^(13aa) and R¹, which may be the same or different, isselected from hydrogen and (1-6C)alkyl,

R^(12aa) is selected from amino, (1-6C)alkylamino anddi-[(1-6C)alkyl]amino,

and wherein any CH₂ or CH₃ group within an X² group, optionally bears oneach said CH₂ or CH₃ group one or more halogeno substituents,

and wherein any CH₂ group which is attached to 2 carbon atoms or any CH₃group which is attached to a carbon atom within a X² substituentoptionally bears on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylamino anddi-[(1-6C)alkyl]amino;

(ddd) X² is a group of the formula —(CR¹²R¹³)_(q)—,

q is 1, 2, 3 or 4 (particularly 1 or 2, more particularly 1),

each of R¹² and R¹³, which may be the same or different, is selectedfrom hydrogen and (1-6C)alkyl, provided that at least one of the R¹² orR¹³ groups in X² is (1-6C)alkyl,

and wherein any CH₂ or CH₃ group within an X² group, optionally bears oneach said CH₂ or CH₃ group one or more halogeno substituents,

and wherein any CH₂ group which is attached to 2 carbon atoms or any CH₃group which is attached to a carbon atom within a X² substituentoptionally bears on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy, and (1-6C)alkoxy;

(eee) X² is selected from a group of the formula —(CR¹²R¹³)—,—(CR¹²R¹³CH₂)—, —(CR²R³CH₂CH₂)—, —(CH₂CR¹²R¹³)— and —(CH₂CH₂CR²R³)—,

each of R¹² and R¹³, which may be the same or different, is selectedfrom hydrogen and (1-6C)alkyl,

and wherein any CH₂ or CH₃ group within X², optionally bears on eachsaid CH₂ or CH₃ group one or more halogeno substituents,

and wherein any CH₂ group which is attached to 2 carbon atoms or any CH₃group which is attached to a carbon atom within a X² substituentoptionally bears on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylamino anddi-[(1-6C)alkyl]amino;

(fff) X² is selected from a group of the formula —(CR¹²R¹³)—,—(CR²R³CH₂)—, —(CR¹²R¹³CH₂CH₂)—, —(CH₂CR¹²R¹³)— and —(CH₂CH₂CR¹²R¹³)—,

each of R¹² and R¹³, which may be the same or different, is selectedfrom hydrogen and (1-6C)alkyl, provided that at least one of R¹² or R¹³is a branched (1-6C)alkyl group,

and wherein any CH₂ or CH₃ group within X², optionally bears on eachsaid CH₂ or CH₃ group one or more halogeno substituents,

and wherein any CH₂ group which is attached to 2 carbon atoms or any CH₃group which is attached to a carbon atom within a X² substituentoptionally bears on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylamino anddi-[(1-6C)alkyl]amino;

(ggg) X² is selected from a group of the formula —(CR¹²R¹³)—,—(CR²R³CH₂)—, —(CR²R³CH₂CH₂)—, —(CH₂CR¹²R¹³)— and —(CH₂CH₂CR¹²R¹³)—,

each of R¹² and R¹³, which may be the same or different, is selectedfrom hydrogen and (1-6C)alkyl, provided that at least one of R¹² or R¹³in X² is a branched alkyl group, which branched alkyl group ispreferably selected from iso-propyl, iso-butyl, sec-butyl andtert-butyl,

and wherein any CH₂ or CH₃ group within X², optionally bears on eachsaid CH₂ or CH₃ group one or more fluoro or chloro substituents,

and wherein any CH₂ group which is attached to 2 carbon atoms or any CH₃group which is attached to a carbon atom within a X² substituentoptionally bears on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy and (1-3C)alkoxy;

(hhh) X² is selected from a group of the formula —CH₂—, —CH₂CH₂—,—CH₂CH₂CH₂—-(CR¹²R¹³)—, —(CR¹²R¹³CH₂)— and —(CH₂CR¹²R¹³)-

wherein each of R¹² and R¹³, which may be the same or different, isselected from hydrogen, (1-4C)alkyl, hydroxy-(1-4C)alkyl and(1-4C)alkoxy-(1-4C)alkyl, provided that R¹² and R¹³ are not bothhydrogen;

(iii) X² is selected from a group of the formula —CH₂—, —CH₂CH₂—,—(CHR^(12a))-, —(CHR^(12a)CH₂)—, —(C(R^(12a))₂CH₂)—, —(CH₂C(R^(12a))₂)-and —(CH₂CHR^(12b))-,

wherein each R²³, which may be the same or different, is selected from(1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-3C)alkoxy-(1-4C)alkyl,amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl anddi-[(1-4C)alkyl]-amino-(1-4C)alkyl,

and wherein R^(12b) is selected from hydroxy, amino, (1-4C)alkyl,(1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]-amino,hydroxy-(1-4C)alkyl, (1-3C)alkoxy-(1-4C)alkyl, amino-(1-4C)alkyl,(1-4C)alkylamino-(1-4C)alkyl and di-[(1-4C)alkyl]-amino-(1-4C)alkyl;

(jjj) X² is selected from a group of the formula —CH₂—, —CH₂CH₂—,—(CHR^(12a))—, —(CHR^(12a)CH₂)— and —(CH₂CHR^(12b))-

wherein R^(12a) is selected from hydrogen, (1-4C)alkyl,hydroxy-(1-4C)alkyl, (1-3C)alkoxy-(1-4C)alkyl, amino-(1-4C)alkyl,(1-4C)alkylamino-(1-4C)alkyl and di-[(1-4C)alkyl]-amino-(1-4C)alkyl,

and wherein R^(12b) is selected from hydrogen, hydroxy, amino,(1-4C)alkyl, (1-4C)alkoxy, hydroxy-(1-4C)alkyl,(1-3C)alkoxy-(1-4C)alkyl, amino-(1-4C)alkyl,(1-4C)alkylamino-(1-4C)alkyl and di-[(1-4C)alkyl]-amino-(1-4C)alkyl;

(kkk) X² is selected from a group of the formula —CH₂—, —CH₂CH₂—,—(CHR^(12a))—, —(CHR^(12a)CH₂)—, —(C(R^(12a))₂CH₂)—, —(CH₂C(R^(12a))₂)-and —(CH₂CHR^(12b))-,

wherein each R²³, which may be the same or different, is (1-4C)alkyl,

and wherein R^(12b) is selected from amino, (1-4C)alkylamino anddi-[(1-4C)alkyl]-amino;

(lll) X² is selected from a group of the formula —(CHR^(12a))-,—(CHR^(12a)CH₂)—, —(C(R^(12a))₂CH₂)—, —(CH₂C(R^(12a))₂)- and—(CH₂CHR^(12b))-,

wherein each R^(12a), which may be the same or different, is (1-4C)alkyl(particularly (1-3C)alkyl),

and wherein R^(12b) is selected from amino, (1-4C)alkylamino anddi-[(1-4C)alkyl]-amino (particularly R^(12b) is selected from(1-4C)alkylamino and di-[(1-4C)alkyl]-amino, more particularlydi-[(1-3C)alkyl]-amino);

(mmm) X² is selected from a group of the formula —CH₂—, —CH₂CH₂—,—(CHR¹²)—, —(CHR¹²CH₂)— and —(CH₂CHR¹²)—

wherein R¹² is selected from hydrogen, (1-4C)alkyl, hydroxy-(1-4C)alkyl,(1-3C)alkoxy-(1-4C)alkyl, amino-(1-4C)alkyl,(1-4C)alkylamino-(1-4C)alkyl and di-[(1-4C)alkyl]-amino-(1-4C)alkyl;

(nnn) X² is selected from a group of the formula —CH₂—, —CH₂CH₂—,—(CHR^(12a))-, —(CHR^(12a)CH₂)—, —(C(R^(12a))₂CH₂)—, —(CH₂C(R^(12a))₂)-and —(CH₂CHR^(12a))-,

wherein each R²³, which may be the same or different, is (1-4C)alkyl;

(ooo) X² is selected from a group of the formula —(CHR^(12a))-,—(CHR^(12a)CH₂)—, —(C(R¹²a)₂CH₂)—, —(CH₂C(R^(12a))₂)- and—(CH₂CHR^(12a))- (particularly, X² is —(CHR^(12a))-),

wherein each R²³, which may be the same or different, is (1-4C)alkyl;

(ppp) X² is selected from a group of the formula —(CH₂)_(q)—, wherein qis 1, 2 or 3, particularly q is 1 or 2, more particularly 1;(qqq) Z is selected from hydroxy, amino, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxy, (1-6C)alkylsulfonyl,(1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylaminoand a group of the formula:

Q⁶-X⁹-

wherein X⁹ is a direct bond or is selected from O, N(R¹⁶), SO₂ andSO₂N(R¹⁶), wherein R¹⁶ is hydrogen or (1-6C)alkyl, and Q⁶ is(3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl orheterocyclyl-(1-4C)alkyl,

provided that when X⁹ is a direct bond, Q⁶ is heterocyclyl,

and provided that when m, p and q are all 0, then Z is heterocyclyl,

and wherein any heterocyclyl group in Z is a monocyclic fully saturated4, 5, 6 or 7-membered heterocyclyl group containing 1 or 2 heteroatomsselected from oxygen, nitrogen and sulfur,

and wherein and wherein any CH₂ or CH₃ group within a Z group, otherthan a CH₂ group within a heterocyclyl ring, optionally bears on eachsaid CH₂ or CH₃ group one or more halogeno or (1-6C)alkyl substituentsor a substituent selected from hydroxy, cyano, amino, carboxy,carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,(1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino,

and wherein any heterocyclyl group within a Z substituent optionallybears one or more (for example 1, 2 or 3) substitutents which may be thesame or different, selected from halogeno, trifluoromethyl, cyano,nitro, hydroxy, amino, formyl, mercapto, (1-6C)alkyl, (2-6C)alkenyl,(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl,(1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,(2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:

-X¹⁰-R¹⁸

wherein X¹⁰ is a direct bond or is selected from O, CO, SO₂ and N(R¹⁹),wherein R¹⁹ is hydrogen or (1-4C)alkyl, and R¹⁸ is halogeno-(1-4C)alkyl,hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl,amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyl andN,N-di-[(1-4C)alkyl]amino-(1-4C)alkyl;

(rrr) Z is selected from hydroxy, amino, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxy and a group of the formula:

Q⁶-X⁹-

wherein X⁹ is a direct bond or is selected from O and N(R¹⁶), whereinR¹⁶ is hydrogen or (1-6C)alkyl, and Q⁶ is (3-7C)cycloalkyl,(3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl orheterocyclyl-(1-4C)alkyl,

provided that when X⁹ is a direct bond, Q⁶ is heterocyclyl,

and provided that when m, p and q are all 0, then Z is heterocyclyl,

and wherein any heterocyclyl group in Z is a monocyclic non-aromaticfully saturated or partially saturated 4, 5, 6 or 7-memberedheterocyclyl group containing 1 heteroatom selected from oxygen andnitrogen and optionally a further heteroatom selected from oxygen,nitrogen and sulfur,

and wherein and wherein any CH₂ or CH₃ group within a Z group, otherthan a CH₂ group within a heterocyclyl ring, optionally bears on eachsaid CH₂ or CH₃ group one or more halogeno or (1-6C)alkyl substituentsor a substituent selected from hydroxy, cyano, amino, carboxy,carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,(1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino,

and wherein any heterocyclyl group within a Z substituent optionallybears one or more (for example 1, 2 or 3) substitutents which may be thesame or different, selected from halogeno, trifluoromethyl, cyano,nitro, hydroxy, amino, formyl, mercapto, (1-6C)alkyl, (2-6C)alkenyl,(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl,(1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,(2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:

-X¹⁰-R¹⁸

wherein X¹⁰ is a direct bond or is selected from O, CO, SO₂ and N(R¹⁹),wherein R¹⁹ is hydrogen or (1-4C)alkyl, and R¹⁸ is halogeno-(1-4C)alkyl,hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl,amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyl andN,N-di-[(1-4C)alkyl]amino-(1-4C)alkyl;

(sss) Z is selected from hydroxy, amino, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxy and a group of the formula:

Q⁶-X⁹-

wherein X⁹ is a direct bond or is selected from O and N(R¹⁶), whereinR¹⁶ is hydrogen or (1-6C)alkyl, and Q⁶ is (3-7C)cycloalkyl,(3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl orheterocyclyl-(1-4C)alkyl,

provided that when X⁹ is a direct bond, Q⁶ is heterocyclyl,

and provided that when m, p and q are all 0, then Z is heterocyclyl,

and wherein any heterocyclyl group in Z is selected fromtetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl,oxepanyl, pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl,piperazinyl and homopiperazinyl, which heterocyclyl group may be carbonor nitrogen linked to the group to which it is attached,

and wherein and wherein any CH₂ or CH₃ group within a Z group, otherthan a CH₂ group within a heterocyclyl ring, optionally bears on eachsaid CH₂ or CH₃ group one or more halogeno or (1-6C)alkyl substituentsor a substituent selected from hydroxy, cyano, amino, carboxy,carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,(1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino,

and wherein any heterocyclyl group within a Z substituent optionallybears one or more (for example 1, 2 or 3) substitutents which may be thesame or different, selected from halogeno, trifluoromethyl, cyano,nitro, hydroxy, amino, formyl, mercapto, (1-6C)alkyl, (2-6C)alkenyl,(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl,(1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,(2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:

-X¹⁰-R¹⁸

wherein X¹⁰ is a direct bond or is selected from O, CO, SO₂ and N(R¹⁹),wherein R¹⁹ is hydrogen or (1-4C)alkyl, and R¹⁸ is halogeno-(1-4C)alkyl,hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl,amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyl andN,N-di-[(1-4C)alkyl]amino-(1-4C)alkyl;

(ttt) Z is selected from hydroxy, amino, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxy and a group of the formula:

Q⁶-X⁹

wherein X⁹ is a direct bond and Q⁶ is heterocyclyl,

and provided that when m, p and q are all 0, then Z is heterocyclyl(preferably carbon linked to X¹),

and wherein any heterocyclyl group in Z is selected from azetidinyl,tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl,oxepanyl, pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl,piperazinyl and homopiperazinyl,

and wherein and wherein any CH₂ or CH₃ group within a Z group optionallybears on each said CH₂ or CH₃ group one or more halogeno or (1-6C)alkylsubstituents or a substituent selected from hydroxy and (1-6C)alkoxy,

and wherein any heterocyclyl group within a Z substituent optionallybears one or more (for example 1, 2 or 3) substitutents which may be thesame or different, selected from halogeno, trifluoromethyl, cyano,nitro, hydroxy, amino, formyl, (1-6C)alkyl, (2-6C)alkenyl,(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl,(1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino and(2-6C)alkanoyl;

(uuu) Z is selected from hydroxy, amino, (1-6C)alkylamino,hydroxy-(2-6C)alkylamino, (1-4C)alkoxy-(2-6C)alkylamino,di-[(1-6C)alkyl]amino, N—[hydroxy-(2-6C)alkyl]-N-(1-6C)alkylamino,N-[(1-4C)alkoxy-(2-6C)alkyl]-N-(1-6C)alkylamino,di-[hydroxy-(2-6C)alkyl]-amino, di-[(1-4C)alkoxy-(2-6C)alkyl]amino,N-[(1-4C)alkoxy-(2-6C)alkyl]-N—[hydroxy-(2-6C)alkyl]-amino,(1-6C)alkoxy, hydroxy-(2-6C)alkoxy, (1-4C)alkoxy-(2-6C)alkoxy,azetidin-1-yl, pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino,homopiperidin-1-yl homopiperazin-1-yl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyland a group of the formula:

Q⁶-X⁹-

wherein X⁹ is selected from O and N(R¹⁶), wherein R¹⁶ is hydrogen or(1-4C)alkyl, and Q⁶ is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-4C)alkyl,(3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl orheterocyclyl-(1-4C)alkyl,

and wherein any heterocyclyl group in Q⁶ is selected fromtetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl,oxepanyl, pyrrolidinyl, morpholinyl, tetrahydro-1,4-thiazinyl,piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, whichheterocyclyl group may be carbon or nitrogen linked to the group towhich it is attached,

and provided that when m, p and q are all 0, then Z is heterocyclyl,preferably one of the above mentioned heterocyclyl groups that may berepresented by Q⁶, (which heterocyclyl group is preferably carbon linkedto X¹),

and wherein and wherein any CH₂ or CH₃ group within a Z group, otherthan a CH₂ group within a heterocyclyl ring, optionally bears on eachsaid CH₂ or CH₃ group one or more halogeno or (1-6C)alkyl substituentsor a substituent selected from hydroxy, cyano, amino, carboxy,carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,(1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino,

and wherein any heterocyclyl group within a Z substituent optionallybears one or more (for example 1, 2 or 3) substitutents which may be thesame or different, selected from halogeno, trifluoromethyl, cyano,nitro, hydroxy, amino, formyl, mercapto, (1-6C)alkyl, (2-6C)alkenyl,(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl,(1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,(2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:

-X¹⁰-R¹⁸

wherein X¹⁰ is a direct bond or is selected from O, CO, SO₂ and N(R¹⁹),wherein R¹⁹ is hydrogen or (1-4C)alkyl, and R¹⁸ is halogeno-(1-4C)alkyl,hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl,amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyl andN,N-di-[(1-4C)alkyl]amino-(1-4C)alkyl;

(vvv) Z is selected from amino, (1-6C)alkylamino,hydroxy-(2-6C)alkylamino, (1-4C)alkoxy-(2-6C)alkylamino,di-[(1-6C)alkyl]amino, N—[hydroxy-(2-6C)alkyl]-N-(1-6C)alkylamino,N-[(1-4C)alkoxy-(2-6C)alkyl]-N-(1-6C)alkylamino,di-[hydroxy-(2-6C)alkyl]-amino, di-[(1-4C)alkoxy-(2-6C)alkyl]amino,N-[(1-4C)alkoxy-(2-6C)alkyl]-N—[hydroxy-(2-6C)alkyl]-amino,azetidin-1-yl, pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino,homopiperidin-1-yl and homopiperazin-1-yl,

and wherein and wherein any CH₂ or CH₃ group within a Z group,optionally bears on each said CH₂ or CH₃ group one or more fluorosubstituents or a substituent selected from hydroxy, cyano, amino,(2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino anddi-[(1-6C)alkyl]amino,

and wherein any heterocyclyl group within a Z substituent optionallybears one or more (for example 1, 2 or 3) substitutents which may be thesame or different, selected from halogeno, cyano, hydroxy, amino,(1-4C)alkyl, (1-4C)alkoxy, (2-4C)alkanoyl, (1-4C)alkylamino anddi-[(1-4C)alkyl]amino,

and provided that when m, p and q are all 0, then Z is one of the abovementioned heterocyclyl groups that may be represented by Z, such aspyrrolidin-1-yl or piperidino (preferably the sum of m+p+q is at least1);

(www) Z is selected from hydroxy, (1-6C)alkoxy, hydroxy-(2-6C)alkoxy,(1-4C)alkoxy-(2-6C)alkoxy, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,1,3-dioxolanyl, 1,4-dioxanyl, tetrahydropyranyl and a group of theformula:

Q⁶-X⁹-

wherein X⁹ is O, and Q⁶ is (3-7C)cycloalkyl,(3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl orheterocyclyl-(1-4C)alkyl, wherein any heterocyclyl group represented byQ⁶ is preferably selected from tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, 1,3-dioxolanyl, 1,4-dioxanyl andtetrahydropyranyl,

and provided that when m, p and q are all 0, then Z is selected fromtetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1,3-dioxolanyl,1,4-dioxanyl, tetrahydropyranyl and oxepanyl,

and wherein any CH₂ or CH₃ group within a Z group, optionally bears oneach said CH₂ or CH₃ group one or more fluoro substituents or asubstituent selected from hydroxy, cyano, amino, (2-6C)alkenyl,(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino,

and wherein any heterocyclyl group within a Z substituent optionallybears one or more (for example 1, 2 or 3) substitutents which may be thesame or different, selected from halogeno, cyano, hydroxy, amino,(1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]amino;

(xxx) Z is selected from hydroxy, amino, (1-6C)alkylamino,hydroxy-(2-6C)alkylamino, (1-4C)alkoxy-(2-6C)alkylamino,di-[(1-6C)alkyl]amino, N—[hydroxy-(2-6C)alkyl]-N-(1-6C)alkylamino,N-[(1-4C)alkoxy-(2-6C)alkyl]-N-(1-6C)alkylamino,di-[hydroxy-(2-6C)alkyl]-amino, di-[(1-4C)alkoxy-(2-6C)alkyl]amino,N-[(1-4C)alkoxy-(2-6C)alkyl]-N—[hydroxy-(2-6C)alkyl]-amino,(1-6C)alkoxy, hydroxy-(2-6C)alkoxy and (1-4C)alkoxy-(2-6C)alkoxy,

and wherein the sum of m+p+q is at least 1;

(yyy) Z is selected from hydroxy, amino, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxy, hydroxy-(2-6C)alkoxy and(1-4C)alkoxy-(2-6C)alkoxy, and the sum of m+p+q is at least 1;(zzz) Z is selected from hydroxy, (1-6C)alkoxy, hydroxy-(2-6C)alkoxy and(1-4C)alkoxy-(2-4C)alkoxy), and the sum of m+p+q is at least 1;(aaaa) Z is selected from hydroxy, methoxy, ethoxy, 2-hydroxyethoxy,2-methoxyethoxy, amino, methylamino, ethylamino,N-(2-hydroxyethyl)amino, N-(2-methoxyethyl)amino, dimethylamino,N-methyl-N-ethylamino, di-ethylamino, N-(2-hydroxyethyl)-N-methylamino,N-(2-hydroxyethyl)-N-ethylamino, N,N-di-(2-hydroxyethyl)amino,N-(2-methoxyethyl)-N-methylamino, N-(2-methoxyethyl)-N-ethylamino,pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino,tetrahydrofuranyl and tetrahydropyranyl,

and wherein any heterocyclyl group within Z optionally bears 1 or 2substituents, which may be the same or different, selected from fluoro,chloro, hydroxy, (1-4C)alkyl, (2-4C)alkanoyl and (1-4C)alkoxy,

and provided that when m, p and q are all 0, then Z is one of the abovementioned heterocyclyl groups that may be represented by Z, such aspyrrolidin-1-yl, tetrahydrofuranyl or piperidino (preferably the sum ofm+p+q is at least 1);

(bbbb) Z is selected from pyrrolidin-1-yl, piperidino, piperazin-1-yl,morpholino, homopiperidin-1-yl, homopiperazin-1-yl, (particularly Z isselected from pyrrolidin-1-yl, piperidino, piperazin-1-yl andmorpholino),

and wherein the heterocyclyl group within Z optionally bears one or more(for example 1, 2 or 3) substituents, which may be the same or differentselected from fluoro, chloro, cyano, hydroxy, amino, carbamoyl,(1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino,N-(1-4C)alkylcarbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl, acetyl,propionyl, 2-fluoroethyl, 2-hydroxyethyl, 2-methoxyethyl, cyanomethyl,hydroxyacetyl, aminoacetyl, methylaminoacetyl, ethylaminoacetyl,dimethylaminoacetyl and N-methyl-N-ethylaminoacetyl (preferably the sumof m+p+q is at least 1);

(cccc) Z is selected from hydroxy, (1-4C)alkoxy, tetrahydrofuranyl andtetrahydropyranyl

and wherein any tetrahydrofuranyl or tetrahydropyranyl group within Zoptionally bears one or two substituents, which may be the same ordifferent selected from fluoro, chloro, hydroxy, (1-4C)alkyl and(1-4C)alkoxy,

and provided that when m, p and q are all 0, then Z is selected fromtetrahydrofuranyl and tetrahydropyranyl (preferably the sum of m+p+q isat least 1);

(dddd) Z is hydroxy or (1-4C)alkoxy (particularly Z is hydroxy), and thesum of m+p+q is at least 1;(eeee) Z is as defined in any of (qqq) to (dddd) above,

and wherein X² is selected from —CH₂—, —CH₂CH₂—, —(CR¹²R¹³)—,—(CR¹²R¹³CH₂)—, —(CH₂CR¹²R¹³)— and (3-6C)cycloalkenylene (for examplecyclopropylene such as cyclopropylidene),

wherein each of R¹² and R¹³, which may be the same or different, isselected from hydrogen, (1-4C)alkyl, hydroxy-(1-4C)alkyl, and(1-3C)alkoxy-(1-4C)alkyl, provided that R¹² and R¹³ are not bothhydrogen,

and wherein X¹ is CO;

(ffff) Z is as defined in any of (qqq) to (dddd) above;

X² is selected from a group of the formula —CH₂—, —CH₂CH₂—,—(CHR^(12a))-, —(CHR^(12a)CH₂)—, —(C(R^(12a))₂CH₂)—, —(CH₂C(R^(12a))₂)-and —(CH₂CHR^(12b))- (particularly, X² is —(CHR^(12a))),

wherein each R^(12a), which may be the same or different, is selectedfrom (1-4C)alkyl, hydroxy-(1-4C)alkyl and (1-3C)alkoxy-(1-4C)alkyl,

and wherein R^(12b) is selected from hydroxy, amino, (1-4C)alkyl,(1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]-amino,hydroxy-(1-4C)alkyl, (1-3C)alkoxy-(1-4C)alkyl, amino-(1-4C)alkyl,(1-4C)alkylamino-(1-4C)alkyl and di-[(1-4C)alkyl]-amino-(1-4C)alkyl; andwherein X¹ is CO;

(gggg) Z is selected from hydroxy and (1-4C)alkoxy,

X² is selected from a group of the formula —CH₂—, —CH₂CH₂—,—(CHR^(12a))—, —(CHR^(12a)CH₂)—, —(C(R^(12a))₂CH₂)—, —(CH₂C(R^(12a))₂)-and —(CH₂CHR^(12b))- (particularly, X² is —(CHR^(12a))),

wherein each R²³, which may be the same or different, is (1-4C)alkyl,

and wherein R^(12b) is selected from hydroxy, amino, (1-4C)alkyl,(1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]-amino, and whereinX¹ is CO;

(hhhh) Z-X²—X¹ is hydroxy-(2-4C)alkanoyl, for example hydroxyacetyl,2-hydroxypropionyl or 3-hydroxypropionyl, particularly Z-X²—X¹ is2-hydroxypropionyl);(iiii) Z-X²—X¹ is (1-4C)alkoxy-(2-4C)alkanoyl, for examplemethoxyacetyl, 2-methoxypropionyl or 3-methoxypropionyl);(jjj) Z-X²-X¹ is selected from amino-(2-4C)alkanoyl,(1-4C)alkylamino-(2-4C)alkanoyl and di-[(1-4C)alkyl]amino-(2-4C)alkanoyl(for example Z-X²-X¹ is di-[(1-4C)alkyl]amino-acetyl such asdimethylaminoacetyl);(kkkk) Z-X²- is selected from tetrahydrofuranyl, 1,3-dioxolanyl,tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, pyrrolidinyl, morpholinyl,piperidinyl, homopiperidinyl, piperazinyl and homopiperazinyl, whichheterocyclyl is linked to the carbonyl group in Formula I, by a ringcarbon,

and wherein the heterocyclyl group within Z-X² optionally bears 1 or 2substituents, which may be the same or different, selected from fluoro,chloro, hydroxy, (1-4C)alkyl, (1-4C)alkoxy and (2-4C)alkanoyl;

(llll) Z-X²- is selected from tetrahydrofuranyl, 1,3-dioxolanyl,tetrahydropyranyl, 1,4-dioxanyl, oxepanyl (for example Z-X² is selectedtetrahydrofuran-2-yl or tetrahydropyran-2-yl);(mmmm) Z-X²- is selected from pyrrolidinyl, morpholinyl, piperidinyl,homopiperidinyl, piperazinyl and homopiperazinyl, which heterocyclyl islinked to X¹ in Formula I, by a ring carbon,

and wherein the heterocyclyl group within Z-X² optionally bears 1 or 2substituents, which may be the same or different, selected from fluoro,chloro, hydroxy, (1-4C)alkyl, (1-4C)alkoxy and (2-4C)alkanoyl; and

(nnnn) Z-X² is selected from pyrrolidin-1-yl, piperidino, morpholino,piperazin-1-yl, homopiperidin-1-yl and homopiperazin-1-yl,

and wherein the heterocyclyl group within Z-X² optionally bears 1 or 2substituents, which may be the same or different, selected from fluoro,chloro, hydroxy, (1-4C)alkyl, (1-4C)alkoxy and (2-4C)alkanoyl.

A particular embodiment of the present invention is a quinazolinederivative of the Formula I wherein:

R¹ is selected from hydrogen, (1-6C)alkoxy, cyclopropyl-(1-4C)alkoxy,cyclobutyl-(1-4C)alkoxy, cyclopentyl-(1-4C)alkoxy,cyclohexyl-(1-6C)alkoxy, tetrahydrofuranyl-(1-4C)alkoxy andtetrahydropyranyl-(1-4C)alkoxy,

and wherein any CH₂ or CH₃ group within a R¹ substituent optionallybears on each said CH₂ or CH₃ group one or more halogeno substituents,or a substituent selected from hydroxy and (1-4C)alkoxy;

b is 1, 2 or 3;

each R², which may be the same or different, is selected from halogeno(particularly fluoro, chloro or bromo), cyano, hydroxy, trifluoromethyl,(1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl and (1-4C)alkoxy;

Q¹ is piperidin-4-yl;

a is 0, 1 or 2;

each W, which may be the same or different, is selected from halogeno(particularly fluoro), trifluoromethyl, hydroxy, oxo, (1-6C)alkyl,(1-6C)alkoxy, and from a group of the formula:

-X⁸-R¹⁰

wherein X⁸ is a direct bond or is O, and R¹⁰ is halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl or (1-6C)alkoxy-(1-6C)alkyl;

X¹ is CO; and

Z and X² have any of the values hereinbefore defined;

provided that:

when the 4-anilino group in Formula I is 4-bromo-2-fluoroanilino or4-chloro-2-fluoroanilino, R¹ is hydrogen or (1-3C)alkoxy, and X¹ is CO,then a is 0 and Z is selected from hydroxy, amino, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxy, (1-6C)alkylsulfonyl,(1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, anda group of the formula Q⁶-X⁹—, wherein Q⁶-X⁹- is as hereinbeforedefined;

or a pharmaceutically acceptable salt, or a pharmaceutically acceptableester thereof

In this embodiment, a particular value for X² is a group selected from(3-6C)cycloalkylene (such as cyclopropylidene), —CH₂—, —CH₂CH₂—,—CH₂CH₂CH₂—-(CR¹²R¹³)—, —(CR¹²R¹³CH₂)— and —(CH₂CR¹²R¹³)—

wherein each of R¹² and R¹³, which may be the same or different, isselected from hydrogen, (1-4C)alkyl, hydroxy-(1-4C)alkyl, and(1-3C)alkoxy-(1-4C)alkyl, provided that R¹² and R¹³ are not bothhydrogen,

and wherein any CH₂ group within a (3-6C)cycloalkylene group in X²,optionally bears on each said CH₂ or group one or more (1-4C)alkylsubstituents or a substituent selected from hydroxy, (1-4C)alkoxy,hydroxy-(1-4C)alkyl, and (1-3C)alkoxy-(1-4C)alkyl.

In this embodiment, a particular value for Z is a group selected fromhydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxyand a group of the formula:

Q⁶-X⁹-

wherein X⁹ is a direct bond or is selected from O and N(R¹⁶), whereinR¹⁶ is hydrogen or (1-6C)alkyl, and Q⁶ is (3-7C)cycloalkyl,(3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl orheterocyclyl-(1-4C)alkyl,

provided that when X⁹ is a direct bond, Q⁶ is heterocyclyl,

and provided that when m, p and q are all 0, then Z is heterocyclyl,

and wherein any heterocyclyl group in Z is selected fromtetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl,oxepanyl, pyrrolidinyl, morpholinyl, tetrahydro-1,4-thiazinyl,piperidinyl, homopiperidinyl, piperazinyl and homopiperazinyl, whichheterocyclyl group may be carbon or nitrogen linked to the group towhich it is attached,

and wherein and wherein any CH₂ or CH₃ group within a Z group, otherthan a CH₂ group within a heterocyclyl ring, optionally bears on eachsaid CH₂ or CH₃ group one or more halogeno or (1-6C)alkyl substituentsor a substituent selected from hydroxy, cyano, amino, carboxy,carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,(1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino,

and wherein any heterocyclyl group within a Z substituent optionallybears one or more (for example 1, 2 or 3) substitutents which may be thesame or different, selected from halogeno, trifluoromethyl, cyano,nitro, hydroxy, amino, formyl, mercapto, (1-6C)alkyl, (2-6C)alkenyl,(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl,(1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,(2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:

-X¹⁰-R¹⁸

wherein X¹⁰ is a direct bond or is selected from O, CO, SO₂ and N(R¹⁹),wherein R¹⁹ is hydrogen or (1-4C)alkyl, and R¹⁸ is halogeno-(1-4C)alkyl,hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl,amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyl andN,N-di-[(1-4C)alkyl]amino-(1-4C)alkyl.

Another particular value for Z in this embodiment is a group selectedfrom hydroxy, amino, (1-6C)alkylamino, hydroxy-(2-6C)alkylamino,(1-4C)alkoxy-(2-6C)alkylamino, di-[(1-6C)alkyl]amino,N—[hydroxy-(2-6C)alkyl]-N-(1-6C)alkylamino,N-[(1-4C)alkoxy-(2-6C)alkyl]-N-(1-6C)alkylamino,di-[hydroxy-(2-6C)alkyl]-amino, di-[(1-4C)alkoxy-(2-6C)alkyl]amino,N-[(1-4C)alkoxy-(2-6C)alkyl]-N—[hydroxy-(2-6C)alkyl]-amino,(1-6C)alkoxy, hydroxy-(2-6C)alkoxy, (1-4C)alkoxy-(2-6C)alkoxy,azetidin-1-yl, pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino,homopiperidin-1-yl homopiperazin-1-yl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, 1,3-dioxolanyl, tetrahydropyranyl and1,4-dioxanyl,

and provided that when m, p and q are all 0, then Z is one of theheterocyclyl groups mentioned above,

and wherein any heterocyclyl group in Z optionally bears 1 or 2substituents, which may be the same or different, selected from fluoro,chloro, hydroxy, (1-4C)alkyl and (1-4C)alkoxy.

Another particular value for Z in this embodiment is a group selectedfrom hydroxy, (1-4C)alkoxy, hydroxy-(2-4C)alkoxy and(1-4C)alkoxy-(2-4C)alkoxy more particularly Z is hydroxy or(1-4C)alkoxy.

In this embodiment a particular value for each R², which may be the sameor different, is a group selected from fluoro, chloro or bromo and(2-4C)alkynyl;

In this embodiment a particular 4-anilino group in Formula I is selectedfrom 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino,3-chloro-2-fluoroanilino, 2-fluoro-5-chloroanilino, 3-bromoanilino and3-ethynylanilino. Still more particularly the anilino group is3-chloro-2-fluoroanilino or 3-bromo-2-fluoroanilino.

Another particular embodiment of the present invention is a quinazolinederivative of the Formula I wherein:

R¹ is selected from (1-4C)alkoxy, hydroxy-(2-4C)alkoxy,(1-3C)alkoxy-(2-4C)alkoxy or from a group of the formula:

Q²-X³-

wherein X³ is O, and Q² is azetidin-1-yl-(2-4C)alkyl,pyrrolidin-1-yl-(2-4C)alkyl, piperidino-(2-4C)alkyl,piperazino-(2-4C)alkyl or morpholino-(2-4C)alkyl,

and wherein any heterocyclyl group within a substituent on R¹ optionallybears 1, 2 or 3 substituents, which may be the same or different,selected from halogeno, hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy,(1-4C)alkylsulfonyl, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, and(2-4C)alkanoyl, and wherein any heterocyclyl group within a substituenton R¹ optionally bears 1 oxo substituent;

b is 1, 2 or 3;

each R², which may be the same or different, is selected from fluoro,chloro, bromo and (2-4C)alkynyl;

Q¹ is piperidin-4-yl;

a is 0 or 1 (preferably 0);

each W, which may be the same or different is selected from halogeno(particularly fluoro), hydroxy, (1-3C)alkyl and (1-3C)alkoxy;

X¹ is CO;

X² is selected from a group of the formula —CH₂—, —CH₂CH₂—,—(CHR^(12a))-, —(CHR^(12a)CH₂)—, —(C(R^(12a))₂CH₂)—, —(CH₂C(R^(12a))₂)-and —(CH₂CHR^(12b))—,

wherein each R^(12a), which may be the same or different, is selectedfrom (1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-3C)alkoxy-(1-4C)alkyl,amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl anddi-[(1-4C)alkyl]-amino-(1-4C)alkyl (particularly R^(12a) is(1-4C)alkyl),

and wherein R^(12b) is selected from hydroxy, amino, (1-4C)alkyl,(1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]-amino,hydroxy-(1-4C)alkyl, (1-3C)alkoxy-(1-4C)alkyl, amino-(1-4C)alkyl,(1-4C)alkylamino-(1-4C)alkyl and di-[(1-4C)alkyl]-amino-(1-4C)alkyl(particularly R^(12b) selected from amino, (1-4C)alkylamino anddi-[(1-4C)alkyl]-amino);

Z is selected from hydroxy, (1-4C)alkoxy, hydroxy-(2-4C)alkoxy and(1-4C)alkoxy-(2-4C)alkoxy, or

Z-X² is selected from tetrahydrofuranyl, tetrahydropyranyl, azetidinyl,pyrrolidinyl, piperidinyl and morpholinyl, wherein Z-X² is linked to X¹by a ring carbon atom, and wherein any heterocyclyl group within Zoptionally bears one or two substituents, which may be the same ordifferent selected from fluoro, chloro, hydroxy, (1-4C)alkyl,(1-4C)alkoxy and (2-4C)alkanoyl;

provided that:

when the 4-anilino group in Formula I is 4-bromo-2-fluoroanilino or4-chloro-2-fluoroanilino and R¹ is (1-3C)alkoxy, then a is 0;

or a pharmaceutically acceptable salt, or a pharmaceutically acceptableester thereof.

In this embodiment a particular value for Z is a group selected fromhydroxy, and (1-4C)alkoxy (for example Z is hydroxy, methoxy or ethoxy).

In this embodiment a particular 4-anilino group in Formula I is selectedfrom 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino,3-chloro-2-fluoroanilino, 2-fluoro-5-chloroanilino, 3-bromoanilino and3-ethynylanilino. Still more particularly the anilino group is3-chloro-2-fluoroanilino or 3-bromo-2-fluoroanilino.

Another particular embodiment of the present invention is a quinazolinederivative of the Formula I wherein:

R¹ is selected from (1-4C)alkoxy, hydroxy-(2-4C)alkoxy,(1-3C)alkoxy-(2-4C)alkoxy or from a group of the formula:

Q²-X³-

wherein X³ is O, and Q² is azetidin-1-yl-(2-4C)alkyl,pyrrolidin-1-yl-(2-4C)alkyl, piperidino-(2-4C)alkyl,piperazino-(2-4C)alkyl or morpholino-(2-4C)alkyl,

and wherein any heterocyclyl group within a substituent on R¹ optionallybears 1, 2 or 3 substituents, which may be the same or different,selected from halogeno, hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy,(1-4C)alkylsulfonyl, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, and(2-4C)alkanoyl,

and wherein any heterocyclyl group within a substituent on R¹ optionallybears 1 oxo substituent (particularly R¹ is selected from (1-4C)alkoxy,hydroxy-(2-4C)alkoxy and (1-3C)alkoxy-(2-4C)alkoxy, more particularly R¹is (1-4C)alkoxy;

b is 1, 2 or 3 (particularly b is 1, more particularly b is 2);

each R², which may be the same or different, is selected from fluoro,chloro, bromo and (2-4C)alkynyl;

Q¹ is piperidin-4-yl;

a is 0 or 1 (preferably 0);

each W, which may be the same or different is selected from halogeno(particularly fluoro), hydroxy, (1-3C)alkyl and (1-3C)alkoxy;

X¹ is CO;

X¹ is a group of the formula —(CR¹²R¹³)_(q)—(CR^(12aa)R^(13aa))-,

q is 1, 2 or 3 (particularly 1 or 2, more particularly 1),

each of R¹², R¹³ and R^(13aa), which may be the same or different, isselected from hydrogen and (1-6C)alkyl,

R^(12aa) is selected from amino, (1-4C)alkylamino anddi-[(1-4C)alkyl]amino;

Z is selected from hydroxy, (1-4C)alkoxy, hydroxy-(2-4C)alkoxy and(1-4C)alkoxy-(2-4C)alkoxy, or

Z-X² is Z is selected from tetrahydrofuranyl, tetrahydropyranyl,azetidinyl, pyrrolidinyl, piperidinyl and morpholinyl, wherein Z-X² islinked to X¹ by a ring carbon atom,

and wherein any heterocyclyl group within Z optionally bears one or twosubstituents, which may be the same or different selected from fluoro,chloro, hydroxy, (1-4C)alkyl, (1-4C)alkoxy and (2-4C)alkanoyl;

provided that:

when the 4-anilino group in Formula I is 4-bromo-2-fluoroanilino or4-chloro-2-fluoroanilino and R¹ is (1-3C)alkoxy, then a is 0;

or a pharmaceutically acceptable salt, or a pharmaceutically acceptableester thereof.

In this embodiment a particular value for Z is a group selected fromhydroxy, and (1-4C)alkoxy (for example Z is hydroxy, methoxy or ethoxy).

In this embodiment a particular 4-anilino group in Formula I is selectedfrom 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino,3-chloro-2-fluoroanilino 3-bromoanilino and 3-ethynylanilino. Moreparticularly in this embodiment the 4-anilino group in Formula I isselected from 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino,3-chloro-2-fluoroanilino and 3-bromoanilino. Still more particularly theanilino group is 3-chloro-2-fluoroanilino or 3-bromo-2-fluoroanilino.Preferably the anilino group is 3-chloro-2-fluoroanilino.

Another particular embodiment of the present invention is a quinazolinederivative of the Formula I wherein:

R¹ is selected from (1-4C)alkoxy, hydroxy-(2-4C)alkoxy,(1-3C)alkoxy-(2-4C)alkoxy or from a group of the formula:

Q²-X³-

wherein X³ is O, and Q² is azetidin-1-yl-(2-4C)alkyl,pyrrolidin-1-yl-(2-4C)alkyl, piperidino-(2-4C)alkyl,piperazino-(2-4C)alkyl or morpholino-(2-4C)alkyl,

and wherein any heterocyclyl group within a substituent on R¹ optionallybears 1, 2 or 3 substituents, which may be the same or different,selected from halogeno, hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy,(1-4C)alkylamino and di-[(1-4C)alkyl]amino (particularly R¹ is selectedfrom (1-4C)alkoxy, hydroxy-(2-4C)alkoxy and (1-3C)alkoxy-(2-4C)alkoxy,more particularly R¹ is (1-4C)alkoxy, for example methoxy, ethoxy,isopropyloxy, still more particularly R¹ is methoxy);

the 4-anilino group in Formula I is selected from3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino,3-chloro-2-fluoroanilino, 2-fluoro-5-chloroanilino, 3-bromoanilino and3-ethynylanilino;

b is 1 or 2;

each R², which may be the same or different, is selected from fluoro,chloro, bromo and ethynyl;

Q¹ is piperidin-4-yl;

a is 0 or 1 (preferably 0);

each W, which may be the same or different is selected from halogeno(particularly fluoro), hydroxy, (1-3C)alkyl and (1-3C)alkoxy;

X¹ is CO;

X² is selected from a group of the formula —(CHR^(12a))-,—(CHR^(12a)CH₂)—, —(C(R^(12a))₂CH₂)—, —(CH₂C(R^(12a))₂)- and—(CH₂CHR^(12b))-,

wherein each R²³, which may be the same or different, is (1-4C)alkyl(particularly (1-3C)alkyl),

and wherein R^(12b) is selected from amino, (1-4C)alkylamino anddi-[(1-4C)alkyl]-amino (particularly R^(12b) is selected from(1-4C)alkylamino and di-[(1-4C)alkyl]-amino, more particularlydi-[(1-3C)alkyl]-amino);

Z is selected from hydroxy, (1-4C)alkoxy, hydroxy-(2-4C)alkoxy and(1-4C)alkoxy-(2-4C)alkoxy, or

Z-X² is selected from tetrahydrofuranyl, tetrahydropyranyl, azetidinyl,pyrrolidinyl, piperidinyl and morpholinyl, which is linked to X¹ by aring carbon atom,

and wherein any heterocyclyl group within Z optionally bears one or twosubstituents, which may be the same or different selected from fluoro,chloro, hydroxy, (1-4C)alkyl, (1-4C)alkoxy and (2-4C)alkanoyl;

or a pharmaceutically acceptable salt, or a pharmaceutically acceptableester thereof.

In this embodiment a particular value for Z is a group selected fromhydroxy, and (1-4C)alkoxy (for example Z is hydroxy, methoxy or ethoxy).

In this embodiment a particular 4-anilino group in Formula I is selectedfrom 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 3-bromoanilinoand 3-ethynylanilino. Still more particularly the anilino group is3-chloro-2-fluoroanilino or 3-bromo-2-fluoroanilino.

Another particular embodiment of the present invention is a quinazolinederivative of the Formula I wherein:

R¹ is selected from (1-4C)alkoxy, hydroxy-(2-4C)alkoxy,(1-3C)alkoxy-(2-4C)alkoxy or from a group of the formula:

Q²-X³-

wherein X³ is O, and Q² is azetidin-1-yl-(2-4C)alkyl,pyrrolidin-1-yl-(2-4C)alkyl, piperidino-(2-4C)alkyl,piperazino-(2-4C)alkyl or morpholino-(2-4C)alkyl,

and wherein any heterocyclyl group within a substituent on R¹ optionallybears 1, 2 or 3 substituents, which may be the same or different,selected from halogeno, hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy,(1-4C)alkylamino and di-[(1-4C)alkyl]amino (particularly R¹ is selectedfrom (1-4C)alkoxy, hydroxy-(2-4C)alkoxy and (1-3C)alkoxy-(2-4C)alkoxy,more particularly R¹ is (1-4C)alkoxy, for example methoxy, ethoxy,isopropyloxy, still more particularly R¹ is methoxy);

the 4-anilino group in Formula I is selected from3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino,3-chloro-2-fluoroanilino, 2-fluoro-5-chloroanilino, 3-bromoanilino and3-ethynylanilino;

Z is hydroxy or (1-4C)alkoxy, (particularly Z is hydroxy, methoxy orethoxy, more particularly Z is hydroxy or methoxy, especially Z ishydroxy);

Q¹ is piperidin-4-yl;

a is 0 or 1 (preferably 0);

each W, which may be the same or different is selected from hydroxy,(1-3C)alkyl and (1-3C)alkoxy;

X¹ is CO;

X² is selected from a group of the formula —(CHR^(12a))- and—(CH₂CHR^(12b))—,

wherein R^(12a) is (1-4C)alkyl (particularly (1-3C)alkyl, moreparticularly methyl),

and wherein R^(12b) is selected from amino, (1-4C)alkylamino anddi-[(1-4C)alkyl]-amino (particularly R^(12b) is selected from(1-3C)alkylamino and di-[(1-3C)alkyl]-amino, more particularlydi-[(1-3C)alkyl]-amino, still more particularly R^(12b) is methylaminoand especially dimethylamino);

or a pharmaceutically acceptable salt, or a pharmaceutically acceptableester thereof.

In this embodiment a particular 4-anilino group in Formula I is selectedfrom 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 3-bromoanilinoand 3-ethynylanilino. Still more particularly the anilino group is3-chloro-2-fluoroanilino or 3-bromo-2-fluoroanilino.

Another particular embodiment of the present invention is a quinazolinederivative of the Formula I wherein:

R¹ is (1-4C)alkoxy (for example methoxy, ethoxy, isopropyloxy,particularly methoxy);

the 4-anilino group in Formula I is selected from3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino,3-chloro-2-fluoroanilino, 2-fluoro-5-chloroanilino, 3-bromoanilino and3-ethynylanilino;

Q¹ is piperidin-4-yl;

a is 0 or 1 (preferably 0);

each W, which may be the same or different is selected from hydroxy,(1-3C)alkyl and (1-3C)alkoxy;

X¹ is CO;

Z-X² is selected from tetrahydrofuranyl, tetrahydropyranyl, azetidinyl,pyrrolidinyl, piperidinyl and morpholinyl (particularly Z-X² istetrahydrofuranyl or pyrrolidinyl), wherein Z-X² is linked to X¹ by aring carbon atom, and wherein any heterocyclyl group within Z optionallybears one or two substituents, which may be the same or differentselected from fluoro, chloro, hydroxy, methyl, methoxy and acetyl;

or a pharmaceutically acceptable salt, or a pharmaceutically acceptableester thereof.

In this embodiment a particular 4-anilino group in Formula I is selectedfrom 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 3-bromoanilinoand 3-ethynylanilino, more particularly the anilino group is selectedfrom 3-bromo-2-fluoroanilino and 3-chloro-2-fluoroanilino.

Another embodiment of the compounds of Formula I is a quinazolinederivative of the Formula Ia:

wherein:

R¹ is selected from hydrogen, (1-6C)alkoxy, cyclopropyl-(1-4C)alkoxy,cyclobutyl-(1-4C)alkoxy, cyclopentyl-(1-4C)alkoxy,cyclohexyl-(1-6C)alkoxy, tetrahydrofuranyl-(1-4C)alkoxy andtetrahydropyranyl-(1-4C)alkoxy,

and wherein any CH₂ or CH₃ group within a R¹ substituent optionallybears on each said CH₂ or CH₃ group one or more halogeno substituents,or a substituent selected from hydroxy and (1-4C)alkoxy;

b₁ is 0, 1 or 2;

each R², which may be the same or different, is selected from halogeno(particularly fluoro, chloro or bromo), cyano, hydroxy, trifluoromethyl,(1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl and (1-4C)alkoxy (particularlyR² is selected from fluoro, chloro, bromo or ethynyl, more particularlyR² is selected from fluoro, chloro and bromo);

R^(2a) is halogeno (particularly fluoro, chloro or bromo, moreparticularly fluoro or chloro, still more particularly chloro or bromo,and especially R^(2a) is chloro);

a is 0, 1 or 2;

each W, which may be the same or different, is selected from halogeno(particularly fluoro), hydroxy, (1-4C)alkyl and (1-4C)alkoxy;

X² is a group of the formula:

-(CR¹²R¹³)_(p)-(Q⁵)_(m)-(CR¹⁴R¹⁵)_(q)-

wherein m is 0 or 1, p is 0, 1, 2, 3 or 4 and q is 0, 1, 2, 3 or 4,

each of R¹², R¹³, R¹⁴ and R¹⁵, which may be the same or different, isselected from hydrogen, (1-6C)alkyl, amino, (1-6C)alkylamino anddi-[(1-6C)alkyl]amino, and Q⁵ is selected from (3-7C)cycloalkylene and(3-7C)cycloalkenylene,

and wherein any CH₂ or CH₃ group within an X² group, optionally bears oneach said CH₂ or CH₃ group one or more halogeno or (1-6C)alkylsubstituents or a substituent selected from hydroxy, cyano, amino,(1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino;

Z is selected from hydroxy, amino, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxy, (1-6C)alkylsulfonyl,(1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, anda group of the formula:

Q⁶-X⁹-

wherein X⁹ is a direct bond or is selected from O, N(R¹⁶), SO₂ andSO₂N(R¹⁶), wherein R¹⁶ is hydrogen or (1-6C)alkyl, and Q⁶ is(3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl orheterocyclyl-(1-4C)alkyl,

provided that when X⁹ is a direct bond, Q⁶ is heterocyclyl,

and provided that when m, p and q are all 0, then Z is heterocyclyl,

and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a Zsubstituent are optionally separated by the insertion into the chain ofa group selected from O, S, SO, SO₂, N(R¹⁷), CO, —C≡C— and —C≡C— whereinR¹⁷ is hydrogen or (1-6C)alkyl,

and wherein and wherein any CH₂ or CH₃ group within any Z group, otherthan a CH₂ group within a heterocyclyl ring, optionally bears on eachsaid CH₂ or CH₃ group one or more halogeno or (1-6C)alkyl substituentsor a substituent selected from hydroxy, cyano, amino, carboxy,carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,(1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino,

and wherein any heterocyclyl group within a Z substituent optionallybears one or more (for example 1, 2 or 3) substitutents which may be thesame or different, selected from halogeno, trifluoromethyl, cyano,nitro, hydroxy, amino, formyl, mercapto, (1-6C)alkyl, (2-6C)alkenyl,(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl,(1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,(2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:

-X¹⁰-R¹⁸

wherein X¹⁰ is a direct bond or is selected from O, CO, SO₂ and N(R¹⁹),wherein R¹⁹ is hydrogen or (1-4C)alkyl, and R¹⁸ is halogeno-(1-4C)alkyl,hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl,amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyl andN,N-di-[(1-4C)alkyl]amino-(1-4C)alkyl;

provided that:

when the 4-anilino group in Formula I is 4-bromo-2-fluoroanilino or4-chloro-2-fluoroanilino and R¹ is (1-3C)alkoxy, then a is 0;

or a pharmaceutically acceptable salt, or a pharmaceutically acceptableester thereof.

Another embodiment of the present invention is a quinazoline derivativeof the Formula Ia as hereinbefore defined, wherein X² is a groupselected from (3-6C)cycloalkylene (such as cyclopropylidene), —CH₂—,—CH₂CH₂—, —CH₂CH₂CH₂—-(CR¹²R¹³)—, —(CR¹²R¹³CH₂)— and —(CH₂CR¹²R¹³)—

wherein each of R¹² and R¹³, which may be the same or different, isselected from hydrogen, (1-4C)alkyl, hydroxy-(1-4C)alkyl, and(1-3C)alkoxy-(1-4C)alkyl, provided that R¹² and R¹³ are not bothhydrogen,

and wherein any CH₂ group within a (3-6C)cycloalkylene group in X²,optionally bears on each said CH₂ or group one or more (1-4C)alkylsubstituents or a substituent selected from hydroxy, (1-4C)alkoxy,hydroxy-(1-4C)alkyl, and (1-3C)alkoxy-(1-4C)alkyl.

Another embodiment of the present invention is a quinazoline derivativeof the Formula 1a as hereinbefore defined, wherein X² is a groupselected from cyclopropylidene, —CH₂—, —CH₂CH₂—, —(CR¹²R¹³)—,—(CR¹²R¹³CH₂)— and —(CH₂CR¹²R¹³)—,

wherein each of R¹² and R¹³, which may be the same or different, isselected from hydrogen and (1-4C)alkyl.

Another embodiment of the present invention is a quinazoline derivativeof the Formula 1a as hereinbefore defined, wherein Z is selected fromhydroxy, amino, (1-6C)alkylamino, hydroxy-(2-6C)alkylamino,(1-4C)alkoxy-(2-6C)alkylamino, di-[(1-6C)alkyl]amino,N—[hydroxy-(2-6C)alkyl]-N-(1-6C)alkylamino,N-[(1-4C)alkoxy-(2-6C)alkyl]-N-(1-6C)alkylamino,di-[hydroxy-(2-6C)alkyl]-amino, di-[(1-4C)alkoxy-(2-6C)alkyl]amino,N-[(1-4C)alkoxy-(2-6C)alkyl]-N—[hydroxy-(2-6C)alkyl]-amino,(1-6C)alkoxy, hydroxy-(2-6C)alkoxy, (1-4C)alkoxy-(2-6C)alkoxy,azetidin-1-yl, pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino,homopiperidin-1-yl homopiperazin-1-yl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, 1,3-dioxolanyl, tetrahydropyranyl and1,4-dioxanyl; or

the group Z-X² is selected from is selected from tetrahydrofuranyl,1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, pyrrolidinyl,morpholinyl, piperidinyl, homopiperidinyl, piperazinyl andhomopiperazinyl, which heterocyclyl represented by Z-X² is linked to thecarbonyl group in Formula Ia, by a ring carbon,

and wherein any heterocyclyl group within Z-X² optionally bears 1 or 2substituents, which may be the same or different, selected from fluoro,chloro, hydroxy, (1-4C)alkyl, (1-4C)alkoxy and (2-4C)alkanoyl.

More particularly, in Formula Ia, Z is selected from hydroxy, methoxy,ethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, amino, methylamino,ethylamino, N-(2-hydroxyethyl)amino, N-(2-methoxyethyl)amino,dimethylamino, N-methyl-N-ethylamino, di-ethylamino,N-(2-hydroxyethyl)-N-methylamino, N-(2-hydroxyethyl)-N-ethylamino,N,N-di-(2-hydroxyethyl)amino, N-(2-methoxyethyl)-N-methylamino,N-(2-methoxyethyl)-N-ethylamino, pyrrolidin-1-yl, piperidino,piperazin-1-yl, morpholino, tetrahydrofuranyl and tetrahydropyranyl; or

the group Z-X² is selected from is selected from tetrahydrofuranyl andtetrahydropyranyl,

and wherein any heterocyclyl group within Z optionally bears 1 or 2substituents, which may be the same or different, selected from fluoro,chloro, hydroxy, (1-4C)alkyl and (1-4C)alkoxy. More particularly Z isselected from hydroxy, (1-4C)alkoxy, hydroxy-(2-4C)alkoxy and(1-4C)alkoxy-(2-4C)alkoxy, still more particularly Z is selected fromhydroxy and (1-4C)alkoxy (for example Z is hydroxy or methoxy).Preferably Z is hydroxy.

Another embodiment of the present invention is a quinazoline derivativeof the Formula I a as hereinbefore defined, wherein:

R^(2a) is bromo or chloro (particularly chloro); and

b is 0 or 1 and R² is at the ortho (2-) position and is halogeno(particularly R² is fluoro); or

b is 0 or 1 and R² is at the para (4-) position and is halogeno(particularly R² is fluoro) and wherein R¹, W, a, X² and Z have any ofthe meanings defined hereinabove in relation to the quinazolinederivative of Formula Ia.

Another particular embodiment of the invention is a quinazolinederivative of the Formula 1a as hereinbefore defined wherein the anilinogroup at the 4-position on the quinazoline ring is selected from3-bromo-2-fluoroanilino, 3-bromoanilino, 3-chloro-4-fluoroanilino and3-chloro-2-fluoroanilino. Particularly the anilino group is selectedfrom 3-chloro-4-fluoroanilino and 3-chloro-2-fluoroanilino. Moreparticularly the anilino group is 3-chloro-4-fluoroanilino. It ispreferred that the anilino group is 3-chloro-2-fluoroanilino. Wherein inthis embodiment R¹, W, a, X² and Z have any of the meanings definedhereinabove in relation to the quinazoline derivative of Formula 1a.

Another embodiment of the compounds of Formula I is a quinazolinederivative of the Formula Ib:

wherein:

R¹ is selected from hydrogen, (1-6C)alkoxy, cyclopropyl-(1-4C)alkoxy,cyclobutyl-(1-4C)alkoxy, cyclopentyl-(1-4C)alkoxy,cyclohexyl-(1-6C)alkoxy, tetrahydrofuranyl-(1-4C)alkoxy andtetrahydropyranyl-(1-4C)alkoxy,

and wherein any CH₂ or CH₃ group within a R¹ substituent optionallybears on each said CH₂ or CH₃ group one or more halogeno substituents,or a substituent selected from hydroxy and (1-4C)alkoxy;

R^(2b) is bromo or chloro (particularly chloro);

a is 0, 1 or 2 (particularly a is 0);

each W, which may be the same or different, is selected from hydroxy,halogeno (particularly fluoro), (1-4C)alkyl and (1-4C)alkoxy;

X² is selected from a group of the formula —CH₂—, —CH₂CH₂—,—CH₂CH₂CH₂—-(CR¹²R¹³)—, —(CR¹²R¹³CH₂)— and —(CH₂CR¹²R¹³)-

wherein each of R¹² and R¹³, which may be the same or different, isselected from hydrogen and (1-4C)alkyl (particularly X² is CH₂, moreparticularly X² is(CHR^(12a))-, wherein R^(12a) is (1-4C)alkyl);

Z is selected from hydroxy, amino, (1-6C)alkylamino,hydroxy-(2-6C)alkylamino, (1-4C)alkoxy-(2-6C)alkylamino,di-[(1-6C)alkyl]amino, N—[hydroxy-(2-6C)alkyl]-N-(1-6C)alkylamino,N-[(1-4C)alkoxy-(2-6C)alkyl]-N-(1-6C)alkylamino,di-[hydroxy-(2-6C)alkyl]-amino, di-[(1-4C)alkoxy-(2-6C)alkyl]amino,N-[(1-4C)alkoxy-(2-6C)alkyl]-N—[hydroxy-(2-6C)alkyl]-amino,(1-6C)alkoxy, hydroxy-(2-6C)alkoxy, (1-4C)alkoxy-(2-6C)alkoxy,azetidin-1-yl, pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino,homopiperidin-1-yl homopiperazin-1-yl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, 1,3-dioxolanyl, tetrahydropyranyl and1,4-dioxanyl; or

the group Z-X² is selected from is selected from tetrahydrofuranyl,1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, pyrrolidinyl,morpholinyl, piperidinyl, homopiperidinyl, piperazinyl andhomopiperazinyl, which heterocyclyl represented by Z-X² is linked to thecarbonyl group in Formula Ib, by a ring carbon,

and wherein any heterocyclyl group within Z-X² optionally bears 1 or 2substituents, which may be the same or different, selected from fluoro,chloro, hydroxy, (1-4C)alkyl, (1-4C)alkoxy and (2-4C)alkanoyl;

or a pharmaceutically acceptable salt, or a pharmaceutically acceptableester thereof.

In an embodiment in Formula Ib, Z is selected from hydroxy, methoxy,ethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, amino, methylamino,ethylamino, N-(2-hydroxyethyl)amino, N-(2-methoxyethyl)amino,dimethylamino, N-methyl-N-ethylamino, di-ethylamino,N-(2-hydroxyethyl)-N-methylamino, N-(2-hydroxyethyl)-N-ethylamino,N,N-di-(2-hydroxyethyl)amino, N-(2-methoxyethyl)-N-methylamino,N-(2-methoxyethyl)-N-ethylamino, pyrrolidin-1-yl, piperidino,piperazin-1-yl, morpholino, tetrahydrofuranyl and tetrahydropyranyl; or

the group Z-X² is selected from is selected from tetrahydrofuranyl andtetrahydropyranyl,

and wherein any heterocyclyl group within Z optionally bears 1 or 2substituents, which may be the same or different, selected from fluoro,chloro, hydroxy, (1-4C)alkyl and (1-4C)alkoxy.

In another embodiment in formula Ib, R¹ is selected from hydrogenmethoxy, ethoxy, propyloxy, isopropyloxy, cyclopropylmethoxy,2-hydroxyethoxy, 2-fluoroethoxy, 2-methoxyethoxy, 2-ethoxyethoxy,2,2-difluoroethoxy and 2,2,2-trifluoroethoxy (Particularly R¹ isselected from hydrogen and (1-3C)alkoxy, more particularly R¹ is(1-3C)alkoxy such as methoxy).

In another embodiment in Formula Ib, R¹ is selected from (1-4C)alkoxy,hydroxy-(2-4C)alkoxy and (1-3C)alkoxy-(2-4C)alkoxy; a is 0; Z isselected from hydroxy, (1-4C)alkoxy, hydroxy-(2-4C)alkoxy and(1-4C)alkoxy-(2-4C)alkoxy, more particularly Z is selected from hydroxyand (1-4C)alkoxy, particularly Z is hydroxy or methoxy (especiallyhydroxy); and X² has any of the meanings defined hereinabove in relationto the quinazoline of the Formula Ib.

Another embodiment of the compounds of Formula I is a quinazolinederivative of the Formula Ic:

wherein:

R^(1a) is selected from (1-3C)alkoxy, hydroxy-(2-3C)alkoxy and(1-3C)alkoxy-(2-3C)alkoxy (particularly R^(1a) is methoxy);

X^(2a) is selected from a group of the formula —(CHR^(12a))- and—(CH₂CHR^(12b))-,

wherein R^(12a) is (1-4C)alkyl (particularly (1-3C)alkyl, moreparticularly methyl),

and wherein R^(12b) is selected from amino, (1-4C)alkylamino anddi-[(1-4C)alkyl]-amino (particularly R^(12b) is selected from(1-3C)alkylamino and di-[(1-3C)alkyl]-amino, more particularlydi-[(1-3C)alkyl]-amino, still more particularly R^(12b) is methylaminoand especially dimethylamino);

Z¹ is selected from hydroxy, (1-4C)alkoxy, hydroxy-(2-4C)alkoxy and(1-4C)alkoxy-(2-4C)alkoxy (particularly Z¹ is hydroxy or (1-4C)alkoxy,for example hydroxy or methoxy), or the group Z¹X^(2a) is selected fromtetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, and piperidinyl,wherein Z¹-X^(2a) is linked to the carbonyl group by a ring carbon atom,

and wherein any heterocyclyl group within Z¹ optionally bears one or twosubstituents, which may be the same or different selected from fluoro,chloro, hydroxy, (1-4C)alkyl, (1-4C)alkoxy and (2-4C)alkanoyl;

or a pharmaceutically acceptable salt, or a pharmaceutically acceptableester thereof.

In this embodiment, preferably Z¹ is selected from hydroxy and(1-4C)alkoxy (particularly Z¹ is hydroxy or methoxy, still moreparticularly Z¹ is hydroxy).

In this embodiment, preferably X^(2a) is a group of the formula—(CHR^(12a))-,

wherein R^(12a) is (1-4C)alkyl (particularly (1-3C)alkyl, moreparticularly methyl),

Another embodiment of the compounds of Formula I is a quinazolinederivative of the Formula Id:

wherein:

R^(1b) is (1-4C)alkoxy,

and wherein any CH₂ or CH₃ group within a R^(1b) substituent optionallybears on each said CH₂ or CH₃ group one or more halogeno substituents,or any CH₂ or CH₃ group within a R¹ which is not attached to an oxygenatom optionally bears on each said CH₂ or CH₃ group a substituentselected from hydroxy and (1-3C)alkoxy;

X^(2b) is selected from a group of the formula —CH₂—, —CH₂CH₂—,—(CHR¹²)—, —(CHR¹²CH₂)— and —(CH₂CHR¹²)—

wherein R¹² is selected from (1-3C)alkyl, hydroxy-(1-3C)alkyl and(1-3C)alkoxy-(1-3C)alkyl; and

Z² is selected from hydroxy, (1-3C)alkoxy, hydroxy-(2-3C)alkoxy,(1-3C)alkoxy-(2-3C)alkoxy, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,1,3-dioxolanyl, tetrahydropyranyl and 1,4-dioxanyl;

and wherein any heterocyclyl group within Z²-X^(2b) optionally bears 1or 2 substituents, which may be the same or different, selected fromfluoro, chloro, hydroxy, (1-3C)alkyl, (1-3C)alkoxy and (2-3C)alkanoyl;

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable ester thereof.

In an embodiment in formula Id, R^(1b) is selected from methoxy, ethoxy,2-hydroxyethoxy, 2-fluoroethoxy, 2-methoxyethoxy, 2-ethoxyethoxy,2,2-difluoroethoxy and 2,2,2-trifluoroethoxy (Particularly R^(1b) is(1-3C)alkoxy such as methoxy).

In another embodiment in formula Id, X^(2b) is selected from a group ofthe formula —CH₂—, —CH₂CH₂— and —(CHR¹²)—, wherein R¹² is selected from(1-3C)alkyl, hydroxy-(1-3C)alkyl and (1-3C)alkoxy-(1-3C)alkyl (forexample R¹² is methyl).

In another embodiment in formula Id, X^(2b) is selected from a group ofthe formula —

CH₂— and —(CHR¹²)—, wherein R¹² is (1-3C)alkyl (for example methyl). Forexample X^(2b) is selected from —CH₂— and —CH(CH₃)—, particularly X^(2b)is —CH(CH₃)—.

In another embodiment in formula Id, Z² is selected from hydroxy and(1-3C)alkoxy (especially hydroxy).

In another embodiment in formula Id, the group Z²-X^(2b)- is selectedfrom hydroxymethyl, methoxymethyl, (S)-1-hydroxyethyl,(R)-1-hydroxyethyl, (S)-1-methoxyethyl, (R)-1-methoxyethyl. Particularlythe group Z²-X^(2b)- is 1-hydroxyethyl, more particularly (S)—1-hydroxyethyl or (R)-1-hydroxyethyl.

In another embodiment in formula Id R^(1b) is (1-3C)alkoxy such asmethoxy; and the group Z²-X^(2b)- is selected from hydroxymethyl,methoxymethyl, (S)-1-hydroxyethyl, (R)-1-hydroxyethyl,(S)-1-methoxyethyl, (R)-1-methoxyethyl. Particularly in this embodimentZ²-X^(2b) is 1-hydroxyethyl, more particularly (S)-1-hydroxyethyl or(R)-1-hydroxyethyl.

A particular compound of the invention is, for example, a quinazolinederivative of the Formula I selected from:

-   N-(3-chloro-2-fluorophenyl)-7-({1-[(dimethylamino)acetyl]piperidin-4-yl}oxy)-6-methoxyquinazolin-4-amine;-   N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2-methoxyethoxy)acetyl]piperidin-4-yl}oxy)quinazolin-4-amine;-   N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{[1-(methoxyacetyl)piperidin-4-yl]oxy}quinazolin-4-amine;-   2-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2-oxoethanol;-   N-(3-chloro-2-fluorophenyl)-7-{[1-(ethoxyacetyl)piperidin-4-yl]oxy}-6-methoxyquinazolin-4-amine;-   N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{[1-(3-methoxypropanoyl)piperidin-4-yl]oxy}quinazolin-4-amine;-   3-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-3-oxopropan-1-ol;-   (2S)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol;-   (2S,3S)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-3-methyl-1-oxopentan-2-ol;-   4-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2-methyl-4-oxobutan-2-ol;-   N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{[1-(tetrahydrofuran-2-ylcarbonyl)piperidin-4-yl]oxy}quinazolin-4-amine;-   3-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2,2-dimethyl-3-oxopropan-1-ol;-   (3R,5S)-1-acetyl-5-{[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]carbonyl}pyrrolidin-3-ol;    and-   N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(4-methylpiperazin-1-yl)acetyl]piperidin-4-yl}oxy)quinazolin-4-amine;    or a pharmaceutically acceptable salt, or pharmaceutically    acceptable ester thereof.

Another particular compound of the invention is, for example, aquinazoline derivative of the Formula I selected from:

-   N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-{[1-(methoxyacetyl)piperidin-4-yl]oxy}quinazolin-4-amine;-   2-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2-oxoethanol;-   N-(3-chloro-2-fluorophenyl)-7-{[1-(ethoxyacetyl)piperidin-4-yl]oxy}-6-methoxyquinazolin-4-amine;-   (2S)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol;    and-   3-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2,2-dimethyl-3-oxopropan-1-ol;-   (2S)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-3,3-dimethyl-1-oxobutan-2-ol;-   N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{[1-(1-methyl-L-prolyl)piperidin-4-yl]oxy}quinazolin-4-amine;-   N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2S)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}oxy)quinazolin-4-amine;-   (2R)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol;-   N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2S)-2-methoxypropanoyl]piperidin-4-yl}oxy)quinazolin-4-amine;-   N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2R)-2-methoxypropanoyl]piperidin-4-yl}oxy)quinazolin-4-amine;-   (2R)-3-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2-(dimethylamino)-3-oxopropan-1-ol;-   (2S)-1-[4-({4-[(3-chloro-4-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol;-   (2S)-1-[4-({4-[3-bromoanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol;-   (2S)-1-[4-({4-[3-bromo-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol;-   (2R)-1-[4-({4-[3-bromo-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol;    and-   (2R)-1-[4-({4-[3-bromoanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol;

or a pharmaceutically acceptable salt, or a pharmaceutically acceptableester thereof.

In a particular embodiment the invention there is provided a quinazolinederivative of the Formula I described herein, or a pharmaceuticallyacceptable salt thereof

A quinazoline derivative of the Formula I, or a pharmaceuticallyacceptable salt, or a pharmaceutically acceptable ester thereof, may beprepared by any process known to be applicable to the preparation ofchemically-related compounds. Suitable processes include, for example,those illustrated in WO94/27965, WO 95/03283, WO 96/33977, WO 96/33978,WO 96/33979, WO 96/33980, WO 96/33981, WO 97/30034, WO 97/38994,WO01/66099, U.S. Pat. No. 5,252,586, EP 520 722, EP 566 226, EP 602 851and EP 635 507. Such processes, when used to prepare a quinazolinederivative of the Formula I are provided as a further feature of theinvention and are illustrated by the following representative processvariants in which, unless otherwise stated, R¹, R², X¹, X², Q¹, W, a, band Z have any of the meanings defined hereinbefore. Necessary startingmaterials may be obtained by standard procedures of organic chemistry.The preparation of such starting materials is described in conjunctionwith the following representative process variants and within theaccompanying Examples. Alternatively necessary starting materials areobtainable by analogous procedures to those illustrated which are withinthe ordinary skill of an organic chemist.

Process (a):

For the preparation of compounds of the Formula I wherein X¹ is CO, thecoupling, conveniently in the presence of a suitable base, of aquinazoline of the formula II or a salt thereof:

wherein R¹, R², W, a, b and Q¹ have any of the meanings definedhereinbefore except that any functional group is protected if necessary,with an acid of the formula III, or a reactive derivative thereof:

Z-X²—COOH  III

wherein Z and X² have any of the meanings defined hereinbefore exceptthat any functional group is protected if necessary;

orProcess (b) the reaction, conveniently in the presence of a suitablebase, of a quinazoline of the formula II, or salt thereof, ashereinbefore defined in relation to Process (a), with a compound of theformula IV:

Z-X²-X¹-L¹  IV

wherein L¹ is a displaceable group and Z, X¹ and X² have any of themeanings defined hereinbefore except that any functional group isprotected if necessary;

orProcess (c) for the preparation of those quinazoline derivatives of theFormula I wherein Z is linked to X² by nitrogen, the reaction,conveniently in the presence of a suitable base, of a compound of theformula V:

wherein L² is a displaceable group and R¹, R², W, X, X², a, b and Q¹have any of the meanings defined hereinbefore except that any functionalgroup is protected if necessary, with a compound of the formula ZH,wherein Z is as hereinbefore defined, except that any functional groupis protected if necessary; or

Process (d)

for the preparation of those quinazoline derivatives which carry a mono-or di-(1-6C)alkylamino group, the reductive amination of thecorresponding quinazoline derivative of the Formula I which contains anN—H group using formaldehyde or a (2-6C)alkanolaldehyde (for exampleacetaldehyde or propionaldehyde); or

Process (e)

for the production of those quinazoline derivatives of the Formula Iwherein R¹ is hydroxy, the cleavage of a quinazoline derivative of theFormula I wherein R¹ is a (1-6C)alkoxy group; or

Process (f)

for the production of those quinazoline derivatives of the Formula Iwherein R¹ is linked to the quinazoline ring by an oxygen atom, bycoupling a compound of the Formula VI:

wherein R², W, X¹, X², Z, a, b and Q¹ have any of the meanings definedhereinbefore except that any functional group is protected if necessary,with a compound of the formula R^(1′)OH, wherein the group R^(1′)O isone of the oxygen linked groups as hereinbefore defined for R¹ (forexample R^(1″) is (1-6C)alkoxy or Q²-O—), except that any functionalgroup is protected if necessary;

and thereafter, if necessary (in any order):

(i) converting a quinazoline derivative of the Formula I into anotherquinazoline derivative of the Formula I;(ii) removing any protecting group that is present by conventionalmeans; and(iii) forming a pharmaceutically acceptable salt, or a pharmaceuticallyacceptable ester. Specific conditions for the above reactions are asfollows:

Conditions for Process (a)

The coupling reaction is conveniently carried out in the presence of asuitable coupling agent, such as a carbodiimide, or a suitable peptidecoupling agent, such as a uronium coupling agent, for exampleO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate (HATU) orO-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyl uronium tetrafluoroborate(TBTU); or a carbodiimide such as dicyclohexylcarbodiimide, optionallyin the presence of a catalyst such as dimethylaminopyridine or4-pyrrolidinopyridine.

The coupling reaction is conveniently carried out in the presence of asuitable base. A suitable base is, for example, an organic amine basesuch as, for example, pyridine, 2,6-lutidine, collidine,4-dimethylaminopyridine, triethylamine, di-isopropylethylamine,N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example,an alkali or alkaline earth metal carbonate, for example sodiumcarbonate, potassium carbonate, cesium carbonate or calcium carbonate.

The reaction is conveniently carried out in the presence of a suitableinert solvent or diluent, for example an ester such as or ethyl acetate,a halogenated solvent such as methylene chloride, chloroform or carbontetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, anaromatic solvent such as toluene, or a dipolar aprotic solvent such asN,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-oneor dimethylsulfoxide. The reaction is conveniently carried out at atemperature in the range, for example, from 0 to 120° C., convenientlyat or near ambient temperature.

By the term “reactive derivative” of the acid of the formula III ismeant a carboxylic acid derivative that will react with the quinazolineof formula II to give the corresponding amide. A suitable reactivederivative of a carboxylic acid of the formula III is, for example, anacyl halide, for example an acyl chloride formed by the reaction of theacid and an inorganic acid chloride, for example thionyl chloride; amixed anhydride, for example an anhydride formed by the reaction of theacid and a chloroformate such as isobutyl chloroformate; an activeester, for example an ester formed by the reaction of the acid and aphenol such as pentafluorophenol, or N-hydroxybenzotriazole; or an acylazide, for example an azide formed by the reaction of the acid and azidesuch as diphenylphosphoryl azide; an acyl cyanide, for example a cyanideformed by the reaction of an acid and a cyanide such asdiethylphosphoryl cyanide. The reaction of such reactive derivatives ofcarboxylic acid with amines (such as a compound of the formula II) iswell known in the art, for Example they may be reacted in the presenceof a base, such as those described above, and in a suitable solvent,such as those described above. The reaction may conveniently beperformed at a temperature as described above.

Preparation of Starting Materials for Process (a)

The quinazoline of the formula II may be obtained by conventionalprocedures, for example as illustrated in Reaction Scheme 1:

wherein R¹, R², Q¹, W, a and b are as hereinbefore defined, except anyfunctional group is protected if necessary, and whereafter anyprotecting group that is present is removed by conventional means, Pg isa suitable hydroxy protecting group, Pg¹ is a suitable amino protectinggroup and L³ is a displaceable group.

Conditions in Reaction Scheme 1

Step(i): Suitable hydroxy protecting groups represented by Pg are wellknown in the art and include those mentioned herein, for example a loweralkanoyl group such as acetyl, or a benzyl group.

A suitable displaceable group L³ is, for example, a halogeno(particularly chloro), alkoxy, aryloxy, mercapto, alkylthio, arylthio,alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl,alkylsulfonyloxy or arylsulfonyloxy group, for example a chloro, bromo,methoxy, phenoxy, pentafluorophenoxy, methylthio, methanesulfonyl,methanesulfonyloxy or toluene-4-sulfonyloxy group. A particulardisplaceable group L³ is chloro.

The reaction is conveniently carried out in the presence of an acid.Suitable acids include, for example hydrogen chloride gas (convenientlydissolved in a suitable solvent such as diethyl ether or dioxane) orhydrochloric acid.

Alternatively the quinazoline derivative of the formula IIa, wherein L³is halogeno (for example chloro), may be reacted with the aniline in theabsence of an acid or a base. In this reaction displacement of thehalogeno leaving group L³ results in the formation of the acid HL³in-situ and the autocatalysis of the reaction.

Alternatively, the reaction of the quinazoline of formula Ia with theaniline may be carried out in the presence of a suitable base. Asuitable base is, for example, an organic amine base such as, forexample, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,triethylamine, di-isopropylethylamine, N-methylmorpholine ordiazabicyclo[5.4.0]undec-7-ene, or, an alkali or alkaline earth metalcarbonate, for example sodium carbonate, potassium carbonate, cesiumcarbonate or calcium carbonate, or an alkali metal hydride, for examplesodium hydride, an alkali metal fluoride such as cesium fluoride, or analkali metal disilazide such as sodium hexamethyldisilazide.

The above reactions are conveniently carried out in the presence of asuitable inert solvent or diluent, for example an alcohol or ester suchas methanol, ethanol, isopropanol or ethyl acetate, a halogenatedsolvent such as methylene chloride, chloroform or carbon tetrachloride,an ether such as tetrahydrofuran or 1,4-dioxan, an aromatic solvent suchas toluene, or a dipolar aprotic solvent such as N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulfoxide oracetonitrile. The above reactions are conveniently carried out at atemperature in the range, for example, 0 to 250° C., conveniently in therange 40 to 80° C. or, preferably, at or near the reflux temperature ofthe solvent when used.

The aniline and the compound of the formula Ia are commerciallyavailable or can be prepared using conventional methods.

Step (ii):

Deprotection using well-known methods. For example when Pg is a benzylgroup it may be removed by treating the compound of formula IIb with asuitable acid such as trifluoroacetic acid. Alternatively a benzylprotecting group may be removed by metal-catalysed hydrogenation, forexample by hydrogenation in the presence of a palladium on carboncatalyst. Similarly, when Pg is a lower alkanoyl group such as acetyl itmay be removed by hydrolysis under basic conditions, for example usingammonia, conveniently as a methanolic ammonia solution.

Step (iiia):

Suitable amino protecting groups Pg₂ are well known, for exampletert-butoxycarbonyl (BOC) groups.

L⁴ is a suitable displaceable group, for example as described above inrelation to L² such as halogeno (particularly chloro or bromo), or analkylsulfonyloxy (particularly methanesulfonyloxy) or arylsulfonyloxy(particularly toluene-4-sulfonyloxy or 4-nitrophenylsulfonyloxy) group.

The reaction of the compound of formula IIc with the compound of formulaIId is conveniently carried out in the presence of a suitable base.Suitable bases include those described above in relation to step (i),such as cesium fluoride or potassium carbonate. The reaction isconveniently carried out in the presence of a suitable inert solvent,for example, a dipolar aprotic solvent such as N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulfoxide oracetonitrile. The above reaction is conveniently carried out at atemperature in the range, for example, 0 to 250° C., conveniently in therange 40 to 80° C. or, preferably, at or near the reflux temperature ofthe solvent when used.

Step (iiib):

An alternative to step (iiia) is the coupling of the compound of formulaIIc with the alcohol of the formula Ile using the Mitsunobu couplingreaction. Suitable Mitsunobu conditions are well known and include, forexample, reaction in the presence of a suitable tertiary phosphine and adi-alkylazodicarboxylate in an organic solvent such as THF, or suitablydichloromethane and in the temperature range 0° C. to 100° C., forexample 0° C. to 60° C., but suitably at or near ambient temperature. Asuitable tertiary phosphine includes for example tri-n-butylphosphine orparticularly tri-phenylphosphine. A suitable di-alkylazodicarboxylateincludes, for example, diethyl azodicarboxylate (DEAD) or suitablydi-tert-butyl azodicarboxylate (DTAD). Details of Mitsunobu reactionsare contained in Tet. Letts., 31, 699, (1990); The Mitsunobu Reaction,D. L. Hughes, Organic Reactions, 1992, Vol. 42, 335-656 and Progress inthe Mitsunobu Reaction, D. L. Hughes, Organic Preparations andProcedures International, 1996, Vol. 28, 127-164.

The compounds of the formulae IId and IIe are commercially available orcan be prepared using conventional methods.

Step (iv):

Removal of the amino protecting group Pg₁ using well known methods. Forexample when Pg₁ is a BOC group, by treatment with a suitable acid suchas trifluoroacetic acid or hydrochloric acid.

In an alternative route to that shown in Reaction Scheme 1, the anilinein step (i) may be reacted with the unprotected variant of the compoundof the formula IIa (i.e. Pg is hydrogen), to give the compound offormula IIc directly.

The compound of formula II may also be prepared according to ReactionScheme 2:

wherein R¹, R², Q¹, W, a, b, L³ and Pg¹ are as hereinbefore defined,except any functional group is protected if necessary, and whereafterany protecting group that is present is removed by conventional means.

Conditions in Reaction Scheme 2 Step (i):

Coupling under Mitsunobu conditions as described above in relation tostep (iiib) in Reaction Scheme 1.

Step (ii):

The reaction is conveniently carried out in the presence of an acid.Suitable acids include, for example hydrogen chloride gas (convenientlydissolved in a suitable solvent such as diethyl ether or dioxane) orhydrochloric acid. The reaction is conveniently carried out in asuitable inert solvent, for example as described in step (i) of ReactionScheme 1. Conveniently, the protecting group Pg¹ is removed in-situ as aresult of the acidic conditions during the aniline coupling reaction,for example when Pg¹ is tert-butoxycarbonyl. Alternatively, theprotecting group may be removed using conventional methods following thereaction.

The quinazoline of the formula IIg is commercially available or can beprepared using conventional methods.

Quinazoline derivatives of the Formula II wherein R¹ isheterocyclyl-(2-6C)alkoxy, wherein the heterocyclyl group is nitrogenlinked to the (2-6C)alkoxy group may be prepared according to ReactionScheme 3:

wherein R¹, R², Q¹, W, X², L¹, L², a, b and Pg¹ are as hereinbeforedefined, except any functional group is protected if necessary, X^(3′)is (2-6C)-alkylene and Q² is a heterocyclyl group containing an NH ringgroup, and whereafter any protecting group that is present is removed byconventional means.

Step (i): L¹ and L² are displaceable groups as defined in relation toProcess (b), for example halogeno such as chloro. The reaction with thecompound of Formula IIj may be carried out under analogous conditions tothose used in Process (b) described herein.

The compound of Formula IIj may be prepared using standard methods, forexample as described in WO03/082831 to give a compound of the FormulaIIj carrying a 2,3-di-haloanilines. Analogous methods may be used toprepare compounds of the Formula IIj by coupling4-chloro-6-hydroxy-7-methoxyquinazoline with the appropriate aniline.

Step (ii): Analogous conditions to Process (b) described herein.Step (iii): Cleavage of the methoxy group under standard conditions forsuch reactions, for example by treatment of the compound of Formula IImwith pyridinium hydrochloride at elevated temperature, for example from60 to 180° C. conveniently about 170° C.Step(iv): Coupling under Mitsunobu conditions as described above inrelation to step (iiib) in Reaction Scheme 1.Step (v): Deprotection to remove the amine protecting group Pg¹, forexample when Pg¹ is tert-butoxycarbonyl, by treating the compound ofFormula (IIo) with a suitable acid such a trifluoroacetic acid.

Reaction Conditions for Process (b)

A suitable displaceable group L¹ includes for example halogeno such aschloro.

The reaction is conveniently performed in the presence of a suitablebase, for example, conveniently in the presence of a suitable base, forexample an organic amine base such as, for example, pyridine,2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine,di-isopropylethylamine, N-methylmorpholine ordiazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkalineearth metal carbonate, for example sodium carbonate, potassiumcarbonate, cesium carbonate, calcium carbonate, or an alkali metalhydride, for example sodium hydride, or an alkali metal disilazide suchas sodium hexamethyldisilazide.

The reaction is conveniently carried out in the presence of a suitableinert solvent or diluent, for example a halogenated solvent such asmethylene chloride, chloroform or carbon tetrachloride, an ether such astetrahydrofuran or 1,4-dioxane, an aromatic solvent such as toluene, ora dipolar aprotic solvent such as N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulfoxide.

The reaction is suitably carried out at a temperature of from 0° C. to30° C., conveniently at ambient temperature.

When Z is hydroxy, the hydroxy group is conveniently protected duringthe reaction with the compound of Formula II. Suitable protecting groupsare well known, for example an alkanoyl group such as acetyl. Theprotecting group may be removed following reaction with the compound ofFormula II by conventional means, for example alkaline hydrolysis in thepresence of a suitable base such as sodium hydroxide.

Compounds of the formula IV are commercially available compounds or theyare known in the literature, or they can be can be prepared by standardprocesses known in the art.

Reaction Conditions for Process (c):

A suitable displaceable group represented by L² includes, for example ahalogeno or a sulfonyloxy group, for example chloro, bromo,methylsulfonyloxy or toluene-4-sulfonyloxy group. A particular group L²is chloro.

The reaction is conveniently performed in the presence of a suitablebase, for example one of the bases described in relation to Process (b).

The reaction is conveniently carried out in the presence of a suitableinert solvent or diluent, for example a halogenated solvent such asmethylene chloride, chloroform or carbon tetrachloride, an ether such astetrahydrofuran or 1,4-dioxane, an ester such as ethyl acetate, anaromatic solvent such as toluene, or a dipolar aprotic solvent such asN,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-oneor dimethylsulfoxide.

The reaction is suitably carried out at a temperature of from 0° C. to80° C., conveniently at ambient temperature.

Preparation of Starting Materials for Process (C)

The compound of formula V used as starting material may be prepared by,for example, reacting, conveniently in the presence of a suitable base,a quinazoline of the formula II, or salt thereof, as hereinbeforedefined in relation to Process (a), with a compound of the formula Va:

L²-X²-X¹-L  Va

wherein X¹ and X² are as hereinbefore defined, and L² and L⁵ aresuitable displaceable groups, provided that L⁵ is more labile than L².

Suitable displaceable groups represented by L² and L⁵ include forexample halogeno such as chloro.

The reaction is conveniently carried out in the presence of a suitablebase and in a suitable inert solvent or diluent as defined above for thereaction of the quinazoline of formula V with the compound of theformula ZH.

The compounds of the formulae ZH and Va are commercially availablecompounds or they are known in the literature, or they can be can beprepared by standard processes known in the art.

Conveniently, in an embodiment of Process (c), a quinazoline of FormulaI may be prepared directly from a quinazoline of formula II by reactingthe quinazoline of formula II with a compound of formula Va and thenreacting the resultant product directly with the compound of the formulaZH without isolating the compound of formula V. This reaction enablesthe quinazoline of Formula I to be prepared in a single reaction vesselstarting with the quinazoline of formula II.

Reaction Conditions for Process (d)

Process (d) may be used to alkylate an NH group in a quinazolinederivative of Formula I, for example when Z is amino or(1-6C)alkylamino, or when the group Z-X² carries an amino or(1-6C)alkylamino substituent. Suitable reductive amination conditionsare well known in the art. For example, for the production of thosequinazoline derivatives of the Formula I which contain an N-methylgroup, the corresponding compound containing a N—H group may be reactedwith formaldehyde in the presence of a suitable reducing agent. Asuitable reducing agent is, for example, a hydride reducing agent, forexample formic acid, an alkali metal aluminium hydride such as lithiumaluminium hydride, or, suitably, an alkali metal borohydride such assodium borohydride, sodium cyanoborohydride, sodium triethylborohydride,sodium trimethoxyborohydride and sodium triacetoxyborohydride. Thereaction is conveniently performed in a suitable inert solvent ordiluent, for example tetrahydrofuran and diethyl ether for the morepowerful reducing agents such as lithium aluminium hydride, and, forexample, methylene chloride or a protic solvent such as methanol andethanol for the less powerful reducing agents such as sodiumtriacetoxyborohydride and sodium cyanoborohydride. The reaction issuitably performed under acidic conditions in the presence of a suitableacid such as hydrogen chloride or acetic acid, a buffer may also be usedto maintain pH at the desired level during the reaction. When thereducing agent is formic acid the reaction is conveniently carried outusing an aqueous solution of the formic acid. The reaction is performedat a temperature in the range, for example, −10 to 100° C., such as 0 to50° C., conveniently, at or near ambient temperature.

Quinazoline derivatives of the Formula I which contain an NH group (forexample when Z is amino or (1-6C)alkylamino) may be prepared using oneof the processes described hereinbefore. For example by coupling acompound of the Formula II with a suitable, optionally protected, aminoacid using Process (a) followed by removal of any protecting groups.

Reaction conditions for Process (e)

The cleavage reaction may conveniently be carried out by any of the manyprocedures known for such a transformation. A particularly suitablecleavage reaction is the treatment of a quinazoline derivative of theFormula I wherein R¹ is a (1-6C)alkoxy group with an alkali metal halidesuch as lithium iodide in the presence of 2,4,6-collidine(2,4,6-trimethylpyridine). We have found that the use of 2,4,6-collidineprovides selective cleavage of the (1-6C)alkoxy group at the C6 positionon the quinazoline ring. The reaction may be carried out in the presenceof a suitable inert solvent or diluent as defined hereinbefore.Conveniently however the reaction may be performed using only the2,4,6-collidine without the need for additional solvents/diluents. Thereaction is suitably carried out at a temperature in the range, forexample, 10 to 170° C., preferably at elevated temperature for example120 to 170° C., for example approximately 130° C.

Reaction Conditions for Process (f)

The coupling reaction is conveniently carried out under Mitsunobuconditions as described above in relation to step (iiib) in ReactionScheme 1.

Preparation of Starting Materials for Process (f)

The compound of Formula VI used as starting material may be prepared by,for example, the cleavage of a quinazoline derivative of the Formula I,wherein R¹ is, for example, methoxy using Process (e) describedhereinbefore. Alternatively, compound of Formula VI may be preparedusing conventional procedures. For example, when X¹ is CO, a compound ofthe Formula VI may be prepared using the method illustrated in ReactionScheme 4:

wherein R¹, R², Q¹, W, X², a, b, Pg and Pg¹ are as hereinbefore defined,except any functional group is protected if necessary, and whereafterany protecting group that is present is removed by conventional means.

Conditions in Reaction Scheme 4

Step (i): Cleavage of methoxy group under analogous conditions to thosedescribed in step (iii) in Reaction Scheme 3.Step (ii) Pg is a suitable hydroxy protecting group as hereinbeforedefined, for example an alkanoyl such as acetyl. The group Pg may beintroduced under standard conditions for example by reacting thecompound of Formula VIb with acetic anhydride.Step (iii) Coupling under Mitsunobu conditions as described above inrelation to step (iiib) in Reaction Scheme 1.Step (iv): Deprotection to remove the protecting group Pg. For examplewhen Pg is acetyl by alkaline hydrolysis in an alcohol, for exampleusing a methanolic ammonia solution.Step (v): Deprotection to remove the amine protecting group Pg¹, forexample when Pg¹ is tert-butoxycarbonyl, by treating the compound ofFormula (VId) with a suitable acid such a trifluoroacetic acid.Step (vi): Coupling with acid Z-X²—COOH using the method described abovefor Process (a).

The quinazoline derivative of the Formula I may be obtained from theabove processes in the form of the free base or alternatively it may beobtained in the form of a salt, an acid addition salt. When it isdesired to obtain the free base from a salt of the compound of FormulaI, the salt may be treated with a suitable base, for example, an alkalior alkaline earth metal carbonate or hydroxide, for example sodiumcarbonate, potassium carbonate, calcium carbonate, sodium hydroxide orpotassium hydroxide, or by treatment with ammonia for example using amethanolic ammonia solution such as 7N ammonia in methanol.

The protecting groups used in the processes above may in general bechosen from any of the groups described in the literature or known tothe skilled chemist as appropriate for the protection of the group inquestion and may be introduced by conventional methods. Protectinggroups may be removed by any convenient method as described in theliterature or known to the skilled chemist as appropriate for theremoval of the protecting group in question, such methods being chosenso as to effect removal of the protecting group with minimum disturbanceof groups elsewhere in the molecule.

Specific examples of protecting groups are given below for the sake ofconvenience, in which “lower”, as in, for example, lower alkyl,signifies that the group to which it is applied preferably has 1-4carbon atoms. It will be understood that these examples are notexhaustive. Where specific examples of methods for the removal ofprotecting groups are given below these are similarly not exhaustive.The use of protecting groups and methods of deprotection notspecifically mentioned are, of course, within the scope of theinvention.

A carboxy protecting group may be the residue of an ester-formingaliphatic or arylaliphatic alcohol or of an ester-forming silanol (thesaid alcohol or silanol preferably containing 1-20 carbon atoms).Examples of carboxy protecting groups include straight or branched chain(1-12C)alkyl groups (for example isopropyl, and tert-butyl); loweralkoxy-lower alkyl groups (for example methoxymethyl, ethoxymethyl andisobutoxymethyl); lower acyloxy-lower alkyl groups, (for exampleacetoxymethyl, propionyloxymethyl, butyryloxymethyl andpivaloyloxymethyl); lower alkoxycarbonyloxy-lower alkyl groups (forexample 1-methoxycarbonyloxyethyl and 1-ethoxycarbonyloxyethyl);aryl-lower alkyl groups (for example benzyl, 4-methoxybenzyl,2-nitrobenzyl, 4-nitrobenzyl, benzhydryl and phthalidyl); tri(loweralkyl)silyl groups (for example trimethylsilyl andtert-butyldimethylsilyl); tri(lower alkyl)silyl-lower alkyl groups (forexample trimethylsilylethyl); and (2-6C)alkenyl groups (for exampleallyl). Methods particularly appropriate for the removal of carboxylprotecting groups include for example acid-, base-, metal- orenzymically-catalysed cleavage.

Examples of hydroxy protecting groups include lower alkyl groups (forexample tert-butyl), lower alkenyl groups (for example allyl); loweralkanoyl groups (for example acetyl); lower alkoxycarbonyl groups (forexample tert-butoxycarbonyl); lower alkenyloxycarbonyl groups (forexample allyloxycarbonyl); aryl-lower alkoxycarbonyl groups (for examplebenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyland 4-nitrobenzyloxycarbonyl); tri(lower alkyl)silyl (for exampletrimethylsilyl and tert-butyldimethylsilyl) and aryl-lower alkyl (forexample benzyl) groups.

Examples of amino protecting groups include formyl, aryl-lower alkylgroups (for example benzyl and substituted benzyl, 4-methoxybenzyl,2-nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl);di-4-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (forexample tert-butoxycarbonyl); lower alkenyloxycarbonyl (for exampleallyloxycarbonyl); aryl-lower alkoxycarbonyl groups (for examplebenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyland 4-nitrobenzyloxycarbonyl); lower alkanoyloxyalkyl groups (forexample pivaloyloxymethyl); trialkylsilyl (for example trimethylsilyland tert-butyldimethylsilyl); alkylidene (for example methylidene) andbenzylidene and substituted benzylidene groups.

Methods appropriate for removal of hydroxy and amino protecting groupsinclude, for example, acid-, base-, metal- or enzymically-catalysedhydrolysis for groups such as 2-nitrobenzyloxycarbonyl, hydrogenationfor groups such as benzyl and photolytically for groups such as2-nitrobenzyloxycarbonyl. For example a tert butoxycarbonyl protectinggroup may be removed from an amino group by an acid catalysed hydrolysisusing trifluoroacetic acid.

The reader is referred to Advanced Organic Chemistry, 4th Edition, by J.March, published by John Wiley & Sons 1992, for general guidance onreaction conditions and reagents and to Protective Groups in OrganicSynthesis, 2^(nd) Edition, by T. Green et al., also published by JohnWiley & Son, for general guidance on protecting groups.

It will be appreciated that certain of the various ring substituents inthe compounds of the present invention may be introduced by standardaromatic substitution reactions or generated by conventional functionalgroup modifications either prior to or immediately following theprocesses mentioned above, and as such are included in the processaspect of the invention. Such reactions and modifications include, forexample, introduction of a substituent by means of an aromaticsubstitution reaction, reduction of substituents, alkylation ofsubstituents and oxidation of substituents. The reagents and reactionconditions for such procedures are well known in the chemical art.Particular examples of aromatic substitution reactions include theintroduction of a nitro group using concentrated nitric acid, theintroduction of an acyl group using, for example, an acyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; the introduction of an alkyl group using an alkyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; and the introduction of a halogeno group.

When a pharmaceutically acceptable salt of a quinazoline derivative ofthe Formula I is required, for example an acid-addition salt, it may beobtained by, for example, reaction of said quinazoline derivative with asuitable acid using a conventional procedure.

When a pharmaceutically acceptable ester of a quinazoline derivative ofthe Formula I is required, it may be obtained by, for example, reactionof said quinazoline derivative with a suitable acid or alcohol using aconventional procedure as herein described in relation to definition ofpharmaceutically acceptable esters.

As mentioned hereinbefore some of the compounds according to the presentinvention may contain one of more chiral centers and may therefore existas stereoisomers (for example when Q¹ is piperidin-3-yl). Stereoisomersmay be separated using conventional techniques, e.g. chromatography orfractional crystallisation. The enantiomers may be isolated byseparation of a racemate for example by fractional crystallisation,resolution or HPLC. The diastereoisomers may be isolated by separationby virtue of the different physical properties of the diastereoisomers,for example, by fractional crystallisation, HPLC or flashchromatography. Alternatively particular stereoisomers may be made bychiral synthesis from chiral starting materials under conditions whichwill not cause racemisation or epimerisation, or by derivatisation, witha chiral reagent. When a specific stereoisomer is isolated it issuitably isolated substantially free for other stereoisomers, forexample containing less than 20%, particularly less than 10% and moreparticularly less than 5% by weight of other stereoisomers.

In the section above relating to the preparation of the quinazolinederivative of Formula I, the expression “inert solvent” refers to asolvent which does not react with the starting materials, reagents,intermediates or products in a manner which adversely affects the yieldof the desired product.

Persons skilled in the art will appreciate that, in order to obtaincompounds of the invention in an alternative and in some occasions, moreconvenient manner, the individual process steps mentioned hereinbeforemay be performed in different order, and/or the individual reactions maybe performed at different stage in the overall route (i.e. chemicaltransformations may be performed upon different intermediates to thoseassociated hereinbefore with a particular reaction).

Certain intermediates used in the processes described above are noveland form a further feature of the present invention. According to afurther aspect of the present invention there is provided a quinazolinederivative of the Formula II as hereinbefore defined wherein a is 2 andeach R², which may be the same or different, is halogeno (particularlyselected from fluoro and chloro) and wherein the R² groups are locatedat the ortho (2-) and meta (3-) positions on the aniline ring; or a saltthereof A particular compound of the Formula II is a compound of theFormula II wherein the anilino group is 3-chloro-2-fluoroanilino or3-bromo-2-fluoroanilino, more particularly the anilino group is3-chloro-2-fluoroanilino. In an embodiment in the compound of FormulaII, or a salt thereof, R¹ is (1-4C)alkoxy; a is 0 or 1; W, when presentis on a ring carbon atom in Q¹ and is selected from (1-4C)alkyl, hydroxyand (1-4C)alkoxy (preferably W is 0); Q¹ is piperidin-4-yl and theanilino group is 3-chloro-2-fluoroanilino or 3-bromo-2-fluoroanilino,more particularly the anilino group is 3-chloro-2-fluoroanilino. Theintermediate of Formula II may be in the form of a salt of theintermediate. Such salts need not be a pharmaceutically acceptable salt.For example it may be useful to form prepare an intermediate in the formof a pharmaceutically non-acceptable salt if, for example, such saltsare useful in the manufacture of a compound of Formula I. Preferably,salts of the compound of Formula II are pharmaceutically acceptablesalts as hereinbefore defined in relation to the quinazoline derivativeof Formula I.

Biological Assays

The inhibitory activities of compounds were assessed in non-cell basedprotein tyrosine kinase assays as well as in cell based proliferationassays before their in vivo activity was assessed in Xenograft studies.

a) Protein Tyrosine Kinase Phosphorylation Assays

This test measures the ability of a test compound to inhibit thephosphorylation of a tyrosine containing polypeptide substrate by EGFR,erbB2 or erbB4 tyrosine kinase enzyme.

Recombinant intracellular fragments of EGFR, erbB2 and erbB4 (accessionnumbers X00588, X03363 and L07868 respectively) were cloned andexpressed in the baculovirus/Sf21 system. Lysates were prepared fromthese cells by treatment with ice-cold lysis buffer (20 mMN2-hydroxyethylpiperizine-N′-2-ethanesulfonic acid (HEPES) pH7.5, 150 mMNaCl, 10% glycerol, 1% Triton X-100, 1.5 mM MgCl₂, 1 mM ethyleneglycol-bis(β-aminoethyl ether) N′,N′,N′,N′-tetraacetic acid (EGTA), plusprotease inhibitors and then cleared by centrifugation.

Constitutive kinase activity of these recombinant proteins wasdetermined by their ability to phosphorylate a synthetic peptide (madeup of a random co-polymer of Glutamic Acid, Alanine and Tyrosine in theratio of 6:3:1). Specifically, Maxisorb 96-well immunoplates were coatedwith synthetic peptide (0.2 μg of peptide in a 200p phosphate bufferedsaline (PBS) solution and incubated at 4° C. overnight). Plates werewashed in 50 mM HEPES pH 7.4 at room temperature to remove any excessunbound synthetic peptide. EGFR or erbB2 activities were assessed byincubation in peptide coated plates for 20 minutes at room temperaturein 100 mM HEPES pH 7.4 at room temperature, adenosine trisphosphate(ATP) at Km concentration for the respective enzyme, 10 mM MnCl₂, 0.1 mMNa₃VO₄, 0.2 mM DL-dithiothreitol (DTT), 0.1% Triton X-100 with testcompound in DMSO (final concentration of 2.5%). Reactions wereterminated by the removal of the liquid components of the assay followedby washing of the plates with PBS-T (phosphate buffered saline with 0.5%Tween 20).

The immobilised phospho-peptide product of the reaction was detected byimmunological methods. Firstly, plates were incubated for 90 minutes atroom temperature with anti-phosphotyrosine primary antibodies that wereraised in the mouse (4G10 from Upstate Biotechnology). Followingextensive washing, plates were treated with Horseradish Peroxidase (HRP)conjugated sheep anti-mouse secondary antibody (NXA931 from Amersham)for 60 minutes at room temperature. After further washing, HRP activityin each well of the plate was measured colorimetrically using22′-Azino-di-[3-ethylbenzthiazoline sulfonate (6)]diammonium saltcrystals (ABTS™ from Roche) as a substrate.

Quantification of colour development and thus enzyme activity wasachieved by the measurement of absorbance at 405 nm on a MolecularDevices ThermoMax microplate reader. Kinase inhibition for a givencompound was expressed as an IC₅₀ value. This was determined bycalculation of the concentration of compound that was required to give50% inhibition of phosphorylation in this assay. The range ofphosphorylation was calculated from the positive (vehicle plus ATP) andnegative (vehicle minus ATP) control values.

b) EGFR Driven KB Cell Proliferation Assay

This assay measures the ability of a test compound to inhibit theproliferation of KB cells (human naso-pharangeal carcinoma obtained fromthe American Type Culture Collection (ATCC)).

KB cells were cultured in Dulbecco's modified Eagle's medium (DMEM)containing 10% foetal calf serum, 2 mM glutamine and non-essential aminoacids at 37° C. in a 7.5% CO₂ air incubator. Cells were harvested fromthe stock flasks using Trypsin/ethylaminediaminetetraacetic acid (EDTA).Cell density was measured using a haemocytometer and viability wascalculated using trypan blue solution before being seeded at a densityof 1.25×10³ cells per well of a 96 well plate in DMEM containing 2.5%charcoal stripped serum, 1 mM glutamine and non-essential amino acids at37° C. in 7.5% CO₂ and allowed to settle for 4 hours.

Following adhesion to the plate, the cells are treated with or withoutEGF (final concentration of 1 ng/ml) and with or without compound at arange of concentrations in dimethylsulfoxide (DMSO) (0.1% final) beforeincubation for 4 days. Following the incubation period, cell numberswere determined by addition of 50 μl of3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)(stock 5 mg/ml) for 2 hours. MTT solution was then tipped off, the plategently tapped dry and the cells dissolved upon the addition of 100 μl ofDMSO.

Absorbance of the solubilised cells was read at 540 nm using a MolecularDevices ThermoMax microplate reader. Inhibition of proliferation wasexpressed as an IC₅₀ value. This was determined by calculation of theconcentration of compound that was required to give 50% inhibition ofproliferation. The range of proliferation was calculated from thepositive (vehicle plus EGF) and negative (vehicle minus EGF) controlvalues.

c) Clone 24 Phospho-erbB2 Cell Assay

This immunofluorescence end point assay measures the ability of a testcompound to inhibit the phosphorylation of erbB2 in a MCF7 (breastcarcinoma) derived cell line which was generated by transfecting MCF7cells with the full length erbB2 gene using standard methods to give acell line that overexpresses full length wild type erbB2 protein(hereinafter ‘Clone 24’ cells).

Clone 24 cells were cultured in Growth Medium (phenol red freeDulbecco's modified Eagle's medium (DMEM) containing 10% foetal bovineserum, 2 mM glutamine and 1.2 mg/ml G418) in a 7.5% CO₂ air incubator at37° C. Cells were harvested from T75 stock flasks by washing once in PBS(phosphate buffered saline, pH7.4, Gibco No. 10010-015) and harvestedusing 2 mls of Trypsin (1.25 mg/ml)/ethylaminediaminetetraacetic acid(EDTA) (0.8 mg/ml) solution. The cells were resuspended in GrowthMedium. Cell density was measured using a haemocytometer and viabilitywas calculated using Trypan Blue solution before being further dilutedin Growth Medium and seeded at a density of 1×10⁴ cells per well (in 100ul) into clear bottomed 96 well plates (Packard, No. 6005182).

3 days later, Growth Medium was removed from the wells and replaced with100 ul Assay Medium (phenol red free DMEM, 2 mM glutamine, 1.2 mg/mlG418) either with or without erbB inhibitor compound. Plates werereturned to the incubator for 4 hrs and then 20 μl of 20% formaldehydesolution in PBS was added to each well and the plate was left at roomtemperature for 30 minutes. This fixative solution was removed with amultichannel pipette, 100 μl of PBS was added to each well and thenremoved with a multichannel pipette and then 50 μl PBS was added to eachwell. Plates were then sealed and stored for up to 2 weeks at 4° C.

Immunostaining was performed at room temperature. Wells were washed oncewith 200 μl PBS/Tween 20 (made by adding 1 sachet of PBS/Tween drypowder (Sigma, No. P3563) to 1 L of double distilled H₂O) using a platewasher then 200 μl Blocking Solution (5% Marvel dried skimmed milk(Nestle) in PBS/Tween 20) was added and incubated for 10 minutes.Blocking Solution was removed using a plate washer and 2001p of 0.5%Triton X-100/PBS was added to permeabalise the cells. After 10 minutes,the plate was washed with 200 μl PBS/Tween 20 and then 2001p BlockingSolution was added once again and incubated for 15 minutes. Followingremoval of the Blocking Solution with a plate washer, 30 μl of rabbitpolyclonal anti-phospho ErbB2 IgG antibody (epitope phospho-Tyr 1248,SantaCruz, No. SC-12352-R), diluted 1:250 in Blocking Solution, wasadded to each well and incubated for 2 hours. Then this primary antibodysolution was removed from the wells using a plate washer followed by two2001p PBS/Tween 20 washes using a plate washer. Then 30PI of Alexa-Fluor488 goat anti-rabbit IgG secondary antibody (Molecular Probes, No.A-11008), diluted 1:750 in Blocking Solution, was added to each well.From now onwards, wherever possible, plates were protected from lightexposure, at this stage by sealing with black backing tape. The plateswere incubated for 45 minutes and then the secondary antibody solutionwas removed from the wells followed by two 200 ul PBS/Tween 20 washesusing a plate washer. Then 100 μl PBS was added to each plate, incubatedfor 10 minutes and then removed using a plate washer. Then a further 100μl PBS was added to each plate and then, without prolonged incubation,removed using a plate washer. Then 50 μl of PBS was added to each welland plates were resealed with black backing tape and stored for up to 2days at 4° C. before analysis.

The Fluorescence signal is each well was measured using an AcumenExplorer Instrument (Acumen Bioscience Ltd.), a plate reader that can beused to rapidly quantitate features of images generated bylaser-scanning. The instrument was set to measure the number offluorescent objects above a pre-set threshold value and this provided ameasure of the phosphorylation status of erbB2 protein. Fluorescencedose response data obtained with each compound was exported into asuitable software package (such as Origin) to perform curve fittinganalysis. Inhibition of erbB2 phosphorylation was expressed as an IC₅₀value. This was determined by calculation of the concentration ofcompound that was required to give 50% inhibition of erbB2phosphorylation signal.

d) In Vivo Xenograft Assay

This assay measures the ability of a test compound to inhibit the growthof a LoVo tumour (colorectal adenocarcinoma obtained from the ATCC) inFemale Swiss athymic mice (Alderley Park, nu/nu genotype).

Female Swiss athymic (nu/nu genotype) mice were bred and maintained inAlderley Park in negative pressure Isolators (PFI Systems Ltd.). Micewere housed in a barrier facility with 12 hr light/dark cycles andprovided with sterilised food and water ad libitum. All procedures wereperformed on mice of at least 8 weeks of age. LoVo tumour cell(colorectal adenocarcinoma obtained from the ATCC) xenografts wereestablished in the hind flank of donor mice by sub cutaneous injectionsof 1×10⁷ freshly cultured cells in 100 μl of serum free media peranimal. On day 5 post-implant, mice were randomised into groups of 7prior to the treatment with compound or vehicle control that wasadministered once daily at 0.1 ml/10 g body weight. Tumour volume wasassessed twice weekly by bilateral Vernier calliper measurement, usingthe formula (length×width)×√(length×width)×(π/6), where length was thelongest diameter across the tumour, and width was the correspondingperpendicular. Growth inhibition from start of study was calculated bycomparison of the mean changes in tumour volume for the control andtreated groups, and statistical significance between the two groups wasevaluated using a Students t test.

Although the pharmacological properties of the compounds of the FormulaI vary with structural change as expected, in general activity possessedby compounds of the Formula I, may be demonstrated at the followingconcentrations or doses in one or more of the above tests (a), (b), (c)and (d):—

Test (a): IC₅₀ in the range, for example, 0.001-1 μM; Test (b): IC₅₀ inthe range, for example, 0.001-5 μM; Test (c): IC₅₀ in the range, forexample, 0.01-5 μM; Test (d): activity in the range, for example, 1-200mg/kg/day;

No physiologically unacceptable toxicity was observed in Test (d) at theeffective dose for compounds tested of the present invention.Accordingly no untoward toxicological effects are expected when acompound of Formula I, or a pharmaceutically acceptable salt thereof, asdefined hereinbefore is administered at the dosage ranges definedhereinafter.

By way of example, using Test (a) (for the inhibition of EGFR tyrosinekinase protein phosphorylation) and Test (b) (the KB cell assay)described above, representative compounds described in the Examplesherein gave the IC₅₀ results shown below in Table A:

TABLE A IC₅₀ (nM) Test (a) (Inhibition of EGFR IC₅₀ (nM) Test (b)Compound tyrosine kinase protein (EGFR driven KB cell of Examplephosphorylation) proliferation assay) 2 76 112 3 41 55 4[1] 30 37 4[3]65 84 4[4] 52 109

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a quinazoline derivative ofthe Formula I, or a pharmaceutically acceptable salt or apharmaceutically acceptable ester thereof, as defined hereinbefore inassociation with a pharmaceutically acceptable diluent or carrier.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular orintramuscular dosing or as a suppository for rectal dosing).

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, forexample from 1 to 30 mg) compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition.

The size of the dose for therapeutic or prophylactic purposes of aquinazoline derivative of the formula I will naturally vary according tothe nature and severity of the conditions, the age and sex of the animalor patient and the route of administration, according to well knownprinciples of medicine.

In using a quinazoline derivative of the formula I for therapeutic orprophylactic purposes it will generally be administered so that a dailydose in the range, for example, 0.1 mg/kg to 75 mg/kg body weight isreceived, given if required in divided doses. In general lower doseswill be administered when a parenteral route is employed. Thus, forexample, for intravenous administration, a dose in the range, forexample, 0.1 mg/kg to 30 mg/kg body weight will generally be used.Similarly, for administration by inhalation, a dose in the range, forexample, 0.05 mg/kg to 25 mg/kg body weight will be used. Oraladministration is however preferred, particularly in tablet form.Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of acompound of this invention.

We have found that the compounds of the present invention possessanti-proliferative properties such as anti-cancer properties that arebelieved to arise from their erbB family receptor tyrosine kinaseinhibitory activity, particularly inhibition of the EGF receptor (erbB1)tyrosine kinase. Furthermore, certain of the compounds according to thepresent invention possess substantially better potency against the EGFreceptor tyrosine kinase, than against other tyrosine kinase enzymes,for example erbB2, VEGF or KDR receptor tyrosine kinases. Such compoundspossess sufficient potency against the EGF receptor tyrosine kinase thatthey may be used in an amount sufficient to inhibit EGF receptortyrosine kinase whilst demonstrating little, or significantly lower,activity against other tyrosine kinase enzymes such as erbB2. Suchcompounds are likely to be useful for the selective inhibition of EGFreceptor tyrosine kinase and are likely to be useful for the effectivetreatment of, for example EGF driven tumours.

Accordingly, the compounds of the present invention are expected to beuseful in the treatment of diseases or medical conditions mediated aloneor in part by erbB receptor tyrosine kinases (especially EGF receptortyrosine kinase), i.e. the compounds may be used to produce an erbBreceptor tyrosine kinase inhibitory effect in a warm-blooded animal inneed of such treatment. Thus the compounds of the present inventionprovide a method for the treatment of malignant cells characterised byinhibition of one or more of the erbB family of receptor tyrosinekinases. Particularly the compounds of the invention may be used toproduce an anti-proliferative and/or pro-apoptotic and/or anti-invasiveeffect mediated alone or in part by the inhibition of erbB receptortyrosine kinases. Particularly, the compounds of the present inventionare expected to be useful in the prevention or treatment of thosetumours that are sensitive to inhibition of one or more of the erbBreceptor tyrosine kinases, such as EGF and/or erbB2 and/or erbB4receptor tyrosine kinases (especially EGF receptor tyrosine kinase) thatare involved in the signal transduction steps which drive proliferationand survival of these tumour cells. Accordingly the compounds of thepresent invention are expected to be useful in the treatment ofpsoriasis, benign prostatic hyperplasia (BPH), atherosclerosis andrestenosis and/or cancer by providing an anti-proliferative effect,particularly in the treatment of erbB receptor tyrosine kinase sensitivecancers. Such benign or malignant tumours may affect any tissue andinclude non-solid tumours such as leukaemia, multiple myeloma orlymphoma, and also solid tumours, for example bile duct, bone, bladder,brain/CNS, breast, colorectal, endometrial, gastric, head and neck,hepatic, lung (particularly non-small-cell lung), neuronal, oesophageal,ovarian, pancreatic, prostate, renal, skin, testicular, thyroid, uterineand vulval cancers.

According to this aspect of the invention there is provided aquinazoline derivative of the Formula I, or a pharmaceuticallyacceptable salt, or a pharmaceutically acceptable ester thereof, for useas a medicament.

According to a further aspect of the invention there is provided aquinazoline derivative of the Formula I, or a pharmaceuticallyacceptable salt, or a pharmaceutically acceptable ester thereof, for usein the production of an anti-proliferative effect in a warm-bloodedanimal such as a human.

Thus according to this aspect of the invention there is provided the useof a quinazoline derivative of the Formula I, or a pharmaceuticallyacceptable salt, or a pharmaceutically acceptable ester thereof asdefined hereinbefore in the manufacture of a medicament for use in theproduction of an anti-proliferative effect in a warm-blooded animal suchas a human.

According to a further feature of this aspect of the invention there isprovided a method for producing an anti-proliferative effect in awarm-blooded animal, such as a human, in need of such treatment whichcomprises administering to said animal an effective amount of aquinazoline derivative of the Formula I, or a pharmaceuticallyacceptable salt, or a pharmaceutically acceptable ester thereof, ashereinbefore defined.

According to a further aspect of the invention there is provided the useof a quinazoline derivative of the Formula I, or a pharmaceuticallyacceptable salt, or a pharmaceutically acceptable ester thereof, asdefined hereinbefore in the manufacture of a medicament for use in theprevention or treatment of those tumours which are sensitive toinhibition of erbB receptor tyrosine kinases, such as EGFR and/or erbB2and/or erbB4 (especially EGFR) tyrosine kinases, that are involved inthe signal transduction steps which lead to the proliferation of tumourcells.

According to a further feature of this aspect of the invention there isprovided a method for the prevention or treatment of those tumours in awarm-blooded animal such as a human which are sensitive to inhibition ofone or more of the erbB family of receptor tyrosine kinases, such asEGFR and/or erbB2 and/or erbB4 (especially EGFR) tyrosine kinases, thatare involved in the signal transduction steps which lead to theproliferation and/or survival of tumour cells which comprisesadministering to said animal an effective amount of a quinazolinederivative of the Formula I, or a pharmaceutically acceptable salt, or apharmaceutically acceptable ester thereof, as defined hereinbefore.

According to a further feature of this aspect of the invention there isprovided a compound of the Formula I, or a pharmaceutically acceptablesalt, or a pharmaceutically acceptable ester thereof, for use in theprevention or treatment of those tumours in a warm-blooded animal suchas a human which are sensitive to inhibition of erbB receptor tyrosinekinases, such as EGFR and/or erbB2 and/or erbB4 (especially EGFR)tyrosine kinases, that are involved in the signal transduction stepswhich lead to the proliferation of tumour cells.

According to a further aspect of the invention there is provided the useof a quinazoline derivative of the Formula I, or a pharmaceuticallyacceptable salt, or a pharmaceutically acceptable ester thereof, asdefined hereinbefore in the manufacture of a medicament for use inproviding a EGFR and/or erbB2 and/or erbB4 (especially a EGFR) tyrosinekinase inhibitory effect in a warm-blooded animal such as a human.

According to a further feature of this aspect of the invention there isprovided a method for providing a EGFR and/or an erbB2 and or an erbB4(especially a EGFR) tyrosine kinase inhibitory effect in a warm-bloodedanimal such as a human which comprises administering to said animal aneffective amount of a quinazoline derivative of the Formula I, or apharmaceutically acceptable salt, or a pharmaceutically acceptable esterthereof, as defined hereinbefore.

According to a further feature of this aspect of the invention there isprovided a compound of the Formula I, or a pharmaceutically acceptablesalt, or a pharmaceutically acceptable ester thereof, for use inproviding a EGFR and/or erbB2 and/or erbB4 (especially a EGFR) tyrosinekinase inhibitory effect in a warm-blooded animal such as a human.

According to a further feature of the present invention there isprovided the use of a quinazoline derivative of the Formula I, or apharmaceutically acceptable salt, or a pharmaceutically acceptable esterthereof, as defined hereinbefore in the manufacture of a medicament foruse in providing a selective EGFR tyrosine kinase inhibitory effect in awarm-blooded animal such as a human.

According to a further feature of this aspect of the invention there isprovided a method for providing a selective EGFR tyrosine kinaseinhibitory effect in a warm-blooded animal such as a human whichcomprises administering to said animal an effective amount of aquinazoline derivative of the Formula I, or a pharmaceuticallyacceptable salt, or a pharmaceutically acceptable ester thereof, asdefined hereinbefore.

According to a further feature of this aspect of the invention there isprovided a compound of the Formula I, or a pharmaceutically acceptablesalt, or a pharmaceutically acceptable ester thereof, for use inproviding a selective EGFR tyrosine kinase inhibitory effect in awarm-blooded animal such as a human.

By “a selective EGFR kinase inhibitory effect” is meant that thequinazoline derivative of Formula I is more potent against EGF receptortyrosine kinase than it is against other kinases. In particular some ofthe compounds according to the invention are more potent against EGFreceptor kinase than it is against other tyrosine kinases such as othererbB receptor tyrosine kinases such erbB2. For example a selective EGFRkinase inhibitor according to the invention is at least 5 times,preferably at least 10 times more potent against EGF receptor tyrosinekinase than it is against erbB2 tyrosine kinase, as determined from therelative IC₅₀ values in suitable assays. For example, by comparing theIC₅₀ value from the KB cell assay (a measure of the EGFR tyrosine kinaseinhibitory activity) with the IC₅₀ value from the Clone 24 phospho-erbB2cell assay (a measure of erb-B2 tyrosine kinase inhibitory activity) fora given test compound as described above.

According to a further aspect of the present invention there is providedthe use of a quinazoline derivative of the Formula I, or apharmaceutically acceptable salt, or a pharmaceutically acceptable esterthereof, as defined hereinbefore in the manufacture of a medicament foruse in the treatment of a cancer (for example a cancer selected fromleukaemia, multiple myeloma, lymphoma, bile duct, bone, bladder,brain/CNS, breast, colorectal, endometrial, gastric, head and neck,hepatic, lung (particularly non-small-cell lung), neuronal, oesophageal,ovarian, pancreatic, prostate, renal, skin, testicular, thyroid, uterineand vulval cancer) in a warm-blooded animal such as a human.

According to a further feature of this aspect of the invention there isprovided a method for treating a cancer (for example a cancer selectedfrom leukaemia, multiple myeloma, lymphoma, bile duct, bone, bladder,brain/CNS, breast, colorectal, endometrial, gastric, head and neck,hepatic, lung (particularly non-small-cell lung), neuronal, oesophageal,ovarian, pancreatic, prostate, renal, skin, testicular, thyroid, uterineand vulval cancer) in a warm-blooded animal, such as a human, in need ofsuch treatment, which comprises administering to said animal aneffective amount of a quinazoline derivative of the Formula I, or apharmaceutically acceptable salt, or a pharmaceutically acceptable esterthereof, as defined hereinbefore.

According to a further aspect of the invention there is provided acompound of the Formula I, or a pharmaceutically acceptable salt, or apharmaceutically acceptable ester thereof, for use in the treatment of acancer (for example selected from leukaemia, multiple myeloma, lymphoma,bile duct, bone, bladder, brain/CNS, breast, colorectal, endometrial,gastric, head and neck, hepatic, lung (particularly non-small-celllung), neuronal, oesophageal, ovarian, pancreatic, prostate, renal,skin, testicular, thyroid, uterine and vulval cancer) in a warm-bloodedanimal such as a human.

As mentioned above the size of the dose required for the therapeutic orprophlyactic treatment of a particular disease will necessarily bevaried depending upon, amongst other things, the host treated, the routeof administration and the severity of the illness being treated.

The anti-proliferative treatment/tyrosine kinase inhibitoryeffect/anti-cancer treatment defined hereinbefore may be applied as asole therapy or may involve, in addition to the compound of theinvention, conventional surgery or radiotherapy or chemotherapy. Suchchemotherapy may include one or more of the following categories ofanti-tumour agents:—

(i) antiproliferative/antineoplastic drugs and combinations thereof, asused in medical oncology, such as alkylating agents (for examplecis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan,chlorambucil, busulphan and nitrosoureas); antimetabolites (for exampleantifolates such as fluoropyrimidines like 5-fluorouracil and tegafur,raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea;antitumour antibiotics (for example anthracyclines like adriamycin,bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C,dactinomycin and mithramycin); antimitotic agents (for example vincaalkaloids like vincristine, vinblastine, vindesine and vinorelbine andtaxoids like taxol and taxotere); and topoisomerase inhibitors (forexample epipodophyllotoxins like etoposide and teniposide, amsacrine,topotecan and camptothecin);(ii) cytostatic agents such as antioestrogens (for example tamoxifen,toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptordown regulators (for example fulvestrant), antiandrogens (for examplebicalutamide, flutamide, nilutamide and cyproterone acetate), LHRHantagonists or LHRH agonists (for example goserelin, leuprorelin andbuserelin), progestogens (for example megestrol acetate), aromataseinhibitors (for example as anastrozole, letrozole, vorazole andexemestane) and inhibitors of 5α-reductase such as finasteride;(iii) agents which inhibit cancer cell invasion (for examplemetalloproteinase inhibitors like marimastat and inhibitors of urokinaseplasminogen activator receptor function);(iv) inhibitors of growth factor function, for example such inhibitorsinclude growth factor antibodies, growth factor receptor antibodies (forexample the anti-erbb2 antibody trastuzumab [Herceptin™] and theanti-erbb1 antibody cetuximab [C225]), farnesyl transferase inhibitors,MEK inhibitors, tyrosine kinase inhibitors and serine/threonine kinaseinhibitors, for example other inhibitors of the epidermal growth factorfamily (for example other EGFR family tyrosine kinase inhibitors such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine(gefitinib, AZD1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib, OSI-774) and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine(CJ 1033)), for example inhibitors of the platelet-derived growth factorfamily and for example inhibitors of the hepatocyte growth factorfamily;(v) antiangiogenic agents such as those which inhibit the effects ofvascular endothelial growth factor, (for example the anti-vascularendothelial cell growth factor antibody bevacizumab [Avastin™],compounds such as those disclosed in International Patent ApplicationsWO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compoundsthat work by other mechanisms (for example linomide, inhibitors ofintegrin αvβ3 function and angiostatin);(vi) vascular damaging agents such as Combretastatin A4 and compoundsdisclosed in International Patent Applications WO 99/02166, WO00/40529,WO 00/41669, WO 01/92224, WO02/04434 and WO02/08213;(vii) antisense therapies, for example those which are directed to thetargets listed above, such as ISIS 2503, an anti-ras antisense;(viii) gene therapy approaches, including for example approaches toreplace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2,GDEPT (gene-directed enzyme pro-drug therapy) approaches such as thoseusing cytosine deaminase, thymidine kinase or a bacterial nitroreductaseenzyme and approaches to increase patient tolerance to chemotherapy orradiotherapy such as multi-drug resistance gene therapy; and(ix) immunotherapy approaches, including for example ex-vivo and in-vivoapproaches to increase the immunogenicity of patient tumour cells, suchas transfection with cytokines such as interleukin 2, interleukin 4 orgranulocyte-macrophage colony stimulating factor, approaches to decreaseT-cell energy, approaches using transfected immune cells such ascytokine-transfected dendritic cells, approaches usingcytokine-transfected tumour cell lines and approaches usinganti-idiotypic antibodies.(x) Cell cycle inhibitors including for example CDK inhibitors (egflavopiridol) and other inhibitors of cell cycle checkpoints (egcheckpoint kinase); inhibitors of aurora kinase and other kinasesinvolved in mitosis and cytokinesis regulation (eg mitotic kinesins);and histone deacetylase inhibitors

Such conjoint treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of thetreatment. Such combination products employ the compounds of thisinvention within the dosage range described hereinbefore and the otherpharmaceutically-active agent within its approved dosage range.

According to this aspect of the invention there is provided apharmaceutical product comprising a quinazoline derivative of theFormula I as defined hereinbefore and an additional anti-tumour agent asdefined hereinbefore for the conjoint treatment of cancer.

Although the compounds of the Formula I are primarily of value astherapeutic agents for use in warm-blooded animals (including man), theyare also useful whenever it is required to inhibit the effects of theerbB receptor tyrosine protein kinases. Thus, they are useful aspharmacological standards for use in the development of new biologicaltests and in the search for new pharmacological agents.

The invention will now be illustrated by the following non limitingexamples in which, unless stated otherwise:

(i) temperatures are given in degrees Celsius (° C.); operations werecarried out at room or ambient temperature, that is, at a temperature inthe range of 18-25° C.;(ii) organic solutions were dried over anhydrous magnesium sulfate orsodium sulfate; evaporation of solvent was carried out using a rotaryevaporator under reduced pressure (600-4000 Pascals; 4.5-30 mmHg) with abath temperature of up to 60° C.;(iii) chromatography means flash chromatography on silica gel; thinlayer chromatography (TLC) was carried out on silica gel plates;(iv) in general, the course of reactions was followed by TLC and/oranalytical LCMS, and reaction times are given for illustration only;(v) final products had satisfactory proton nuclear magnetic resonance(NMR) spectra and/or mass spectral data;(vi) yields are given for illustration only and are not necessarilythose which can be obtained by diligent process development;preparations were repeated if more material was required;(vii) when given, NMR data is in the form of delta values for majordiagnostic protons, given in parts per million (ppm) relative totetramethylsilane (TMS) as an internal standard, determined at theoperating frequency of the NMR apparatus used (300 or 400 MHz), usingperdeuterio dimethyl sulfoxide (DMSO-d₆) as solvent unless otherwiseindicated; the following abbreviations have been used: s, singlet; d,doublet; t, triplet; q, quartet; m, multiplet; b, broad;(viii) chemical symbols have their usual meanings; SI units and symbolsare used;(ix) solvent ratios are given in volume:volume (v/v) terms;(x) mass spectra (MS) were run using a Waters or Micromass electrosprayLC-MS in positive or negative ion mode; values for m/z are given;generally, only ions which indicate the parent mass are reported; andunless otherwise stated, the mass ion quoted is (MH)⁺;(xi) where a synthesis is described as being analogous to that describedin a previous example the amounts used are the millimolar ratioequivalents to those used in the previous example;(xii) where compounds were purified using Mass-Triggered PreparativeLCMS the following conditions were used:

-   -   Column: ThermoHypersil Keystone B-Basic 5μ 21 mm×100 mm    -   Eluant: 7.5 minutes Gradient from 20% to 95% of acetonitrile in        water (buffer 2 g/l of (NH₄)₂CO₃,pH 8.9).    -   Flow rate: 25 ml/min;        (xiii) melting points (mp) were measured using a Buchi B-545        Automated melting point apparatus;        (xiv) unless stated otherwise compounds containing an        asymmetrically substituted carbon atom were not resolved; and        (xv) the following abbreviations have been used:

HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-TetramethyluroniumHexafluoro-Phosphate;

DIPEA: diisopropylethylamine;

DMA: N,N-dimethylacetamide;

DMF: N,N-dimethylformamide;

DCM dichloromethane;

DMSO: dimethylsulfoxide

EtOAc: ethyl acetate;

IPA: isopropyl alcohol;

TBTU: O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyl uroniumtetrafluoroborate;

TFA: trifluoroacetic acid; and

THF: tetrahydrofuran.

EXAMPLE 1N-(3-Chloro-2-fluorophenyl)-7-({1-[(dimethylamino)acetyl]piperidin-4-yl}oxy)-6-methoxyquinazolin-4-amine

N,N-Dimethylaminoacetyl chloride hydrochloride (100 mg) was addedportionwise to a stirred solution ofN-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminedihydrochloride (250 mg, 0.57 mmol) and diisopropylethylamine (300 μl)in methylene chloride (25 ml) at 0° C. The reaction mixture was allowedto stir for 2 hours to room temperature. The reaction mixture was washedwith saturated sodium bicarbonate solution (25 ml), dried (MgSO₄),filtered and evaporated. The residues were purified by columnchromatography eluting with increasingly polar mixtures of methylenechloride/methanol (100/0 to 90/10), followed by methylenechloride/methanol (saturated with ammonia) (90/10). The fractionscontaining the desired product were combined and evaporated under vacuumto give the title product as a white foam (0.125 g, 45%); ¹H NMRSpectrum: (DMSO d₆) 1.50-1.65 (m, 1H); 1.65-1.80 (m, 1H); 1.95-2.15 (m,2H); 2.25 (s, 6H); 3.10-3.50 (m, 4H); 3.75-4.05 (m, 2H); 3.95 (s, 3H);4.90 (m, 1H); 7.30 (m, 1H); 7.35 (s, 1H); 7.40-7.60 (m, 2H); 7.85 (s,1H); 8.40 (s, 1H); 9.65 (s, 1H); Mass Spectrum: (M+H)⁺ 488.

TheN-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminedihydrochloride used as starting material was prepared as follows:

4.0M HCl in Dioxane (4.0 ml) was added to a stirred suspension of7-(benzyloxy)-4-chloro-6-methoxyquinazoline (CAS Registry No162364-72-9, prepared as described in WO98/13354, Example 1) (60 g, 0.2mol) and 3-chloro-2-fluoroaniline (31.96 g, 0.22 mol) in acetonitrile(1200 ml). The reaction mixture was heated at 80° C. for 1 hour thenleft to stand overnight. Acetonitrile (500 ml) was added and theresulting precipitate filtered, washed with acetonitrile (3×500 ml) anddried under vacuum to give7-(benzyloxy)-N-(3-chloro-2-fluorophenyl)-6-methoxyquinazolin-4-aminehydrochloride as a beige solid (85.45 g, 96%); ¹H NMR Spectrum: (DMSOd₆) 4.02 (s, 3H), 5.35 (s, 2H), 7.30-7.60 (m, 9H), 7.65 (m, 1H), 8.38(s, 1H), 8.85 (s, 1H), 11.8 (s, 1H); Mass Spectrum: (M+H)⁺ 410.

A solution of7-(benzyloxy)-N-(3-chloro-2-fluorophenyl)-6-methoxyquinazolin-4-aminehydrochloride (85.45 g, 0.192 mol) in trifluoroacetic acid (300 ml) washeated at 80° C. for 1 hour. The reaction mixture was the evaporated todryness and the residues re-dissolved in methanol (200 ml). Thissolution was then added dropwise to a stirred aqueous solution ofsaturated sodium bicarbonate (500 ml). The resulting precipitate wascollected by filtration, washed with acetonitrile and dried undervacuum. The resulting solids were then purified by hot (100° C.)trituration with a mixture of butanone (500 ml) and MeOH (100 ml),filtered and dried to4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-ol as a cream solid(45 g, 73%); ¹H NMR Spectrum: (DMSO d₆): 3.98 (s, 3H), 7.10 (s, 1H),7.25-7.30 (m, 1H), 7.40-7.50 (m, 1H), 7.50-7.60 (m, 1H), 7.80 (s, 1H),8.30 (s, 1H), 9.55 (s, 1H), 10.32 (s, 1H); Mass Spectrum: (M+H)⁺ 320.

4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-ol (500 mg, 1.565mmol) was dissolved in DMA (20 ml). tert-Butyl(4-methanesulfonyloxy)piperidine-1-carboxylate (436.6 mg, 1.565 mmol)and cesium fluoride (236.3 mg, 1.565 mmol) were added, and the mixturewas heated to 60° C. with stirring. After 18 hours, tert-butyl4-methanesulfonyloxypiperidine-1-carboxylate and cesium fluoride wereagain added in the same quantities to the reaction mixture and heatingwas continued at 60° C. for a further 18 hours. The solvent wasevaporated, and the residue was partitioned between saturated aqueoussodium bicarbonate solution (50 ml) and EtOAc (2×50 ml). The organicswere combined, dried over MgSO₄ and evaporated. The resulting productwas then purified by column chromatography eluting with increasinglypolar mixtures of methylene chloride/EtOAc (100/0 to 0/100). Thefractions containing the desired product were combined and evaporatedunder vacuum to give tert-butyl4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidine-1-carboxylateas a colourless foam (757 mg, 96%); ¹H NMR Spectrum: (DMSO-d₆): 1.52 (s,9H), 1.60-1.80 (m, 2H), 2.02-2.20 (m, 2H), 3.20-3.45 (m, 2H), 3.75-3.92(m, 2H), 4.05 (s, 3H), 4.95 (m, 1H), 7.32-7.45 (m, 2H), 7.55-7.70 (m,2H), 7.92 (s, 1H), 8.50 (s, 1H), 9.73 (s, 1H); Mass Spectrum: (M+H)⁺503.

Trifluoroacetic acid (50 ml) was added to a solution of tert-butyl4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidine-1-carboxylate(750 mg, 1.49 mmol) in methylene chloride (1 ml) and triethylsilane (1ml) and the solution stirred for 1 hour. The reaction mixture was thenevaporated under reduced pressure and the residues re-dissolved in EtOAc(5 ml). This solution was then treated with 1M HCl/diethylether (1 ml)followed by more diethylether (50 ml) to give a white precipitate. Theresulting solids were collected following centrifugation and dried undervacuum to giveN-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminedihydrochloride as a white solid (750 mg); ¹H NMR Spectrum: (DMSO-d₆):2.00-2.20 (m, 2H), 2.25-2.45 (m, 2H), 3.15-3.50 (m, 4H), 4.15 (s, 3H),5.02 (m, 1H), 7.48 (m, 1H), 7.60-7.85 m, 3H), 8.35 (s, 1H), 8.85 (s,1H), 9.56 (bs, 2H); Mass Spectrum: (M+H)⁺ 403.

EXAMPLE 2N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2-methoxyethoxy)acetyl]piperidin-4-yl}oxy)quinazolin-4-amine

N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminedihydrochloride (300 mg), diisopropylethylamine (0.45 ml) and2-(2-methoxyethoxy)acetyl chloride (0.105 g) were stirred in methylenechloride (9 ml) for 2.5 hours. Methylene chloride (20 ml) was added andthe organic layer was washed with aqueous sodium hydroxide (2M, 30 ml)and water (30 ml). The resulting product was purified by flash columnchromatography eluting with methanol (3%) and methylene chloride (97%)gave a foam. This was re-precipitated by stirring in diethyl ether (20ml) to give the title product as a white solid (0.110 g); ¹H NMRSpectrum: (DMSO d₆373K) 1.73 (m, 2H), 2.02 (m, 2H), 3.29 (s, 3H), 3.42(m, 2H), 3.51 (t, J=7 Hz, 2H), 3.60 (t, J=9 Hz, 2H), 3.78 (m, 2H), 3.96(s, 3H), 4.17 (s, 2H), 4.87 (m, 1H), 7.27 (m, 1H), 7.33 (s, 1H), 7.42(m, 1H), 7.58 (m, 1H), 7.85 (s, 1H), 8.39 (s, 1H), 9.29 (br s, 1H); MassSpectrum: (M+H)⁺ 519; melting point 110 to 111° C.

EXAMPLE 3N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-{[1-(methoxyacetyl)piperidin-4-yl]oxy}quinazolin-4-amine

HATU (0.24 g) was added to a solution ofN-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminedihydrochloride (250 mg), diisopropylethylamine (0.37 ml) andmethoxyacetic acid (0.054 g) in methylene chloride (9 ml) and themixture was stirred at room temperature for 2.5 hours. Methylenechloride (20 ml) was added and the organic layer was washed with aqueoussodium hydroxide (2M, 30 ml) and water (30 ml). The resulting productwas purified by flash column chromatography eluting with methanol (3%)and methylene chloride (97%) to give a foam. This was re-precipitated bystirring in diethyl ether (20 ml) to give the title product as a whitesolid (0.200 g); ¹H NMR Spectrum: (DMSO d₆373K) 1.73 (m, 2H), 2.02 (m,2H), 3.37 (s, 3H), 3.41 (m, 2H), 3.77 (m, 2H), 3.98 (s, 3H), 4.09 (s,2H), 4.85 (m, 1H), 7.26 (m, 1H), 7.30 (s, 1H), 7.39 (m, 1H), 7.59 (m,1H), 7.81 (s, 1H), 8.38 (s, 1H), 9.34 (br s, 1H); Mass Spectrum: (M+H)⁺475.

EXAMPLE 4

Using a similar procedure to that described in Example 3,N-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminedihydrochloride was coupled with the appropriate carboxylic acid to givethe compounds shown in Table I:

TABLE 1 No. and Note R  [1] hydroxyacetyl  [2] ethoxyacetyl  [3]3-methoxypropanoyl  [4] 3-hydroxypropanoyl  [5]

 [6]

 [7]

 [8]

 [9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

Notes: In Table 1

 refers to the point of attachment of the carbonyl group in Table 1 tothe nitrogen in the piperidin-4-yl group.

[1]2-[4-({4-[3-Chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2-oxoethanol(0.170 g); ¹H NMR Spectrum: (DMSO d₆373K) 1.78 (m, 2H), 2.02 (m, 2H),3.42 (m, 2H), 3.75 (m, 2H), 3.97 (s, 3H), 4.11 (s, 2H), 4.84 (m, 1H),7.25 (m, 1H), 7.31 (s, 1H), 7.40 (m, 1H), 7.50-7.67 (m, 2H), 7.82 (s,1H), 8.38 (s, 1H), 9.31 (br s, 1H); Mass Spectrum: (M+H)⁺ 461.

[2]N-(3-Chloro-2-fluorophenyl)-7-{[1-(ethoxyacetyl)piperidin-4-yl]oxy}-6-methoxyquinazolin-4-amineas a white solid (0.185 g); ¹H NMR Spectrum: (DMSO d₆ 373K) 1.18 (t, J=8Hz, 3H), 1.74 (m, 2H), 2.03 (m, 2H), 3.41 (m, 2H), 3.52 (q, J=8 Hz, 2H),3.79 (m, 2H), 3.98 (s, 3H), 4.12 (s, 2H), 4.84 (m, 1H), 7.23 (m, 1H),7.32 (s, 1H), 7.42 (m, 1H), 7.58 (m, 1H), 7.81 (s, 1H), 8.38 (s, 1H),9.30 (br s, 1H); Mass Spectrum: (M+H)⁺ 489; melting point 160 to 161° C.

[3]N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-{[1-(3-methoxypropanoyl)piperidin-4-yl]oxy}quinazolin-4-amine(0.155 g); ¹H NMR Spectrum: (DMSO d₆373K) 1.73 (m, 2H), 2.01 (m, 2H),2.62 (t, J=9 Hz, 2H), 3.28 (s, 3H), 3.41 (m, 2H), 3.60 (t, J=9 Hz, 2H),3.79 (m, 2H), 3.97 (s, 3H), 4.82 (m, 1H), 7.24 (m, 1H), 7.30 (s, 1H),7.40 (m, 1H), 7.58 (m, 1H), 7.81 (s, 1H), 8.38 (s, 1H), 9.30 (br s, 1H);Mass Spectrum: (M+H)⁺ 489; melting point 184 to 185° C.

[4]3-[4-({4-[3-Chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-3-oxopropan-1-ol(0.061 g); ¹H NMR Spectrum: (DMSO d₆373K) 1.72 (m, 2H), 2.01 (m, 2H),2.62 (t, J=8 Hz, 2H), 3.40 (m, 2H), 3.71 (m, 2H), 3.80 (m, 2H), 3.96 (s,3H), 4.13 (t, J=5 Hz, 1H), 4.83 (m, 1H), 7.28 (m, 1H), 7.31 (s, 1H),7.42 (m, 1H), 7.59 (m, 1H), 7.83 (s, 1H), 8.39 (s, 1H), 9.29 (br s, 1H);Mass Spectrum: (M+H)⁺ 475; melting point 128 to 132° C.

[5] Following the coupling reaction between (2S)-2-hydroxypropanoic acidandN-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminedihydrochloride the product was purified by flash column chromatographyeluting with methylene chloride/7N ammonia solution in methanol(98.6/1.4) to give a foam. This was re-precipitated by stirring indiethyl ether (20 ml) to give(2S)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-olas an amorphous white solid (0.092 g) (melting point 107 to 111° C.).Recrystallisation from acetonitrile gave a crystalline solid (meltingpoint 189 to 191° C.); ¹H NMR Spectrum: (DMSO d₆) 1.19 (d, 3H),1.48-1.75 (m, 2H), 1.94-2.13 (m, 2H), 3.21-3.53 (m, 2H), 3.93 (s, 3H),3.78-4.06 (m, 2H), 4.40-4.52 (m, 1H), 4.83-4.99 (m, 2H), 7.28 (dd, 1H),7.33 (s, 1H), 7.42-7.55 (m, 2H), 7.81 (s, 1H), 8.36 (s, 1H), 9.62 (s,1H); Mass Spectrum: (M+H)⁺ 475.

[6] Following the coupling reaction, the product was purified by flashcolumn chromatography eluting with methylene chloride/7N ammoniasolution in methanol (98/2) gave a foam. This was re-precipitated bystirring in diethyl ether (20 ml) to give(2S,3S)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-3-methyl-1-oxopentan-2-olas a white solid (0.244 g); ¹H NMR Spectrum: (DMSO d₆) 0.78 (d, J=7 Hz,3H), 0.91 (t, J=7 Hz, 3H), 1.21 (m, 1H), 1.44 (m, 1H), 1.61 (m, 3H),2.05 (m, 2H), 3.40 (m, 2H), 3.79 (m, 1H), 3.95 (s, 3H), 4.00 (m, 1H),4.28 (m, 1H), 4.43 (m, 1H), 4.93 (m, 1H), 7.29 (m, 1H), 7.36 (s, 1H),7.48 (m, 1H), 7.53 (m, 1H), 7.83 (s, 1H), 8.39 (s, 1H), 9.63 (br s, 1H);Mass Spectrum: (M+H)⁺ 517; melting point 114 to 118° C.

[7] Following the coupling reaction, the product was purified by flashcolumn chromatography eluting with methanol (4%) and methylene chloride(96%) gave a foam. This was re-precipitated by stirring in diethyl ether(20 ml) to give4-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2-methyl-4-oxobutan-2-olas a white solid (0.232 g); ¹H NMR Spectrum: (DMSO d₆) 1.20 (s, 6H),1.54-1.77 (m, 2H), 2.04 (m, 2H), 2.49 (s, 2H), 3.30 (m, 1H), 3.45 (m,1H), 3.86 (m, 1H), 3.96 (s, 3H), 4.00 (m, 1H), 4.88 (s, 1H), 4.91 (1H,m), 7.28 (m, 1H), 7.35 (s, 1H), 7.47 (m, 1H), 7.54 (m, 1H), 7.83 (s,1H), 8.40 (s, 1H), 9.63 (br s, 1H); Mass Spectrum: (M+H)⁺ 503; meltingpoint 196 to 199° C.

[8] Following the coupling reaction, the product was purified by flashcolumn chromatography eluting with methylene chloride/7N ammoniasolution in methanol (98/2) gave a foam. This was re-precipitated bystirring in diethyl ether (20 ml) to giveN-(3-chloro-2-fluorophenyl)-6-methoxy-7-{[1-(tetrahydrofuran-2-ylcarbonyl)piperidin-4-yl]oxy}quinazolin-4-amineas a white solid (0.260 g); ¹H NMR Spectrum: (DMSO d₆ 373K) 1.73 (m,2H), 1.99 (m, 2H), 2.05 (m, 3H), 2.14 (m, 1H), 3.48 (m, 2H), 3.83 (m,4H), 3.99 (s, 3H), 4.69 (t, J=7 Hz, 1H), 4.89 (1H, m), 7.29 (m, 1H),7.37 (s, 1H), 7.43 (m, 1H), 7.60 (m, 1H), 7.83 (s, 1H), 8.39 (s, 1H),9.33 (br s, 1H); Mass Spectrum: (M+H)⁺ 501; melting point 199 to 201° C.

[9] Following the coupling reaction, the product was purified by flashcolumn chromatography eluting with methanol (4%) and methylene chloride(96%) gave a foam. This was re-precipitated by stirring in diethyl ether(20 ml) to give3-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2,2-dimethyl-3-oxopropan-1-olas a white solid (0.244 g). ¹H NMR Spectrum: (DMSO d₆) 1.10 (s, 6H),1.64 (m, 2H), 2.03 (m, 2H), 3.39 (m, 2H), 3.45 (m, 2H), 3.95 (s, 3H),3.98 (m, 2H), 4.54 (t, J=6 Hz, 1H), 4.91 (1H, m), 7.29 (m, 1H), 7.35 (s,1H), 7.48 (m, 1H), 7.53 (m, 1H), 7.83 (s, 1H), 8.39 (s, 1H), 9.64 (br s,1H); Mass Spectrum: (M+H)⁺ 503; melting point 111 to 115° C.

[10](3R,5S)-1-Acetyl-5-{[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]carbonyl}pyrrolidin-3-ol(0.160 g); ¹H NMR Spectrum: (DMSO d₆ 373K) 1.65-1.87 (m, 3H), 1.93 (s,3H), 2.04 (m, 3H), 3.44-3.64 (m, 4H), 3.81 (m, 2H), 3.98 (s, 3H),4.28-4.39 (m, 1H), 4.71 (m, 1H), 4.89 (m, 2H), 7.23 (m, 1H), 7.32 (s,1H), 7.40 (m, 1H), 7.59 (m, 1H), 7.81 (s, 1H), 8.39 (s, 1H), 9.29 (br s,1H); Mass Spectrum: (M+H)⁺ 558; melting point 183 to 187° C.

[11] Following the coupling reaction, the product was purified by flashcolumn chromatography eluting with methanol (3%) and methylene chloride(97%) to give a foam. This was re-precipitated by stirring in diethylether (20 ml) to give(2S)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxobutan-2-ol(0.108 g) as a white solid; ¹H NMR Spectrum: (DMSO d₆373K) 0.91 (t, J=9Hz, 3H), 1.52 (m, 1H), 1.70 (m, 3H), 2.05 (m, 2H), 3.40 (m, 2H), 3.84(m, 2H), 3.94 (s, 3H), 4.28 (m, 1H), 4.40 (m, 1H), 4.88 (m, 1H), 7.26(m, 1H), 7.32 (s, 1H), 7.42 (m, 1H), 7.60 (m, 1H), 7.80 (s, 1H), 8.38(s, 1H), 9.30 (br s, 1H); Mass Spectrum: (M+H)⁺ 489; melting point 152to 153° C.

[12] Following the coupling reaction, the product was purified by flashcolumn chromatography eluting with methylene chloride/7N ammoniasolution in methanol (98/2) gave a foam. This was re-precipitated bystirring in diethyl ether (20 ml) to giveN-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2S)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}oxy)quinazolin-4-amineas a white solid (0.142 g); ¹H NMR Spectrum: (DMSO d₆ 373K) 1.73 (m,2H), 1.99 (m, 2H), 2.05 (m, 3H), 2.14 (m, 1H), 3.48 (m, 2H), 3.83 (m,4H), 3.99 (s, 3H), 4.69 (t, J=7 Hz, 1H), 4.89 (1H, m), 7.29 (m, 1H),7.37 (s, 1H), 7.43 (m, 1H), 7.60 (m, 1H), 7.83 (s, 1H), 8.39 (s, 1H),9.29 (br s, 1H); Mass Spectrum: (M+H)⁺ 501; melting point 198 to 199° C.

[13] Following the coupling reaction, the product was purified by flashcolumn chromatography eluting with methylene chloride/7N ammoniasolution in methanol (98/2) gave a foam. This was re-precipitated bystirring in diethyl ether (20 ml) to giveN-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2R)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}oxy)quinazolin-4-amineas a white solid (0.212 g); ¹H NMR Spectrum: (DMSO d₆ 373K) 1.73 (m,2H), 1.99 (m, 2H), 2.05 (m, 3H), 2.14 (m, 1H), 3.48 (m, 2H), 3.83 (m,4H), 3.99 (s, 3H), 4.69 (t, J=7 Hz, 1H), 4.89 (1H, m), 7.29 (m, 1H),7.37 (s, 1H), 7.43 (m, 1H), 7.60 (m, 1H), 7.83 (s, 1H), 8.39 (s, 1H),9.29 (br s, 1H); Mass Spectrum: (M+H)⁺ 501; melting point 193 to 194° C.

[14] Following the coupling reaction, the product was purified by flashcolumn chromatography eluting with methanol (2.5%) and methylenechloride (97.5%) to give a foam. This was re-precipitated by stirring indiethyl ether (20 ml) to give(2S)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-3,3-dimethyl-1-oxobutan-2-ol(0.026 g) as a white solid; ¹H NMR Spectrum: (DMSO d₆ 373K) 0.94 (s,9H), 1.72 (m, 2H), 2.03 (m, 2H), 3.49 (m, 2H), 3.90 (m, 2H), 3.96 (s,3H), 4.17 (m, 1H), 4.24 (m, 1H), 4.86 (m, 1H), 7.25 (m, 1H), 7.31 (s,1H), 7.40 (m, 1H), 7.59 (m, 1H), 7.82 (s, 1H), 8.38 (s, 1H), 9.29 (br s,1H); Mass Spectrum: (M+H)⁺ 517; melting point 205 to 206° C.

[15]7-({1-[(1-acetylpiperidin-4-yl)carbonyl]piperidin-4-yl}oxy)-N-(3-chloro-2-fluorophenyl)-6-methoxyquinazolin-4-amine;¹H NMR Spectrum: (DMSO+CD₃COOD): 1.33-1.46 (m, 1H); 1.50-1.62 (m, 1H):1.62-1.74 (m, 3H); 1.75-1.85 (m, 1H); 2.00-2.18 (m, 2H); 2.02 (s, 3H);2.62-2.71 (m, 1H); 2.92-3.00 (m, 1H); 3.13 (dd, 1H); 3.30-3.43 (m, 1H);3.47-3.57 (m, 1H); 3.80-3.98 (m, 3H); 4.02 (s, 3H); 4.39 (d, 1H); 4.93(bs, 1H); 7.41 (dd, 1H); 7.49 (s, 1H); 7.58 (dd, 1H); 7.68 (dd, 1H);8.11 (s, 1H); 8.92 (s, 1H); Mass Spectrum: (M+H)⁺ 556.

[16]N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{[1-(tetrahydrofuran-3-ylcarbonyl)piperidin-4-yl]oxy}quinazolin-4-amine;¹H NMR Spectrum: (DMSO+CD₃COOD): 11.64-1.74 (m, 1H); 1.74-1.84 (m, 1H);2.01-2.17 (m, 4H); 3.33-3.55 (m, 3H); 3.66-3.80 (m, 3H); 3.80-3.99 (m,3H); 4.03 (s, 3H); 3.93 (bs, 1H); 7.41 (dd, 1H); 7.48 (s, 1H); 7.58 (dd,1H); 7.67 (dd, 1H); 8.12-(s, 1H); 8.92 (s, 1H); Mass Spectrum: (M+H)⁺501.

[17] Following the coupling reaction, the product was purified by flashcolumn chromatography eluting with methanol (5%) and methylene chloride(95%) to give a foam. This was re-precipitated by stirring in diethylether (20 ml) to give1-{[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]carbonyl}cyclopropanolas a white solid (0.125 g); ¹H NMR Spectrum: (DMSO d₆373K) 0.80 (m, 2H),0.95 (m, 2H), 1.72 (m, 2H), 2.02 (m, 2H), 3.54 (m, 2H), 3.96 (s, 3H),4.00 (m, 2H), 4.87 (m, 1H), 5.90 (s, 1H), 7.25 (m, 1H), 7.31 (s, 1H),7.40 (m, 1H), 7.58 (m, 1H), 7.80 (s, 1H), 8.38 (s, 1H), 9.30 (br s, 1H);Mass Spectrum: (M+H)⁺ 487; melting point 177 to 178° C.

EXAMPLE 5N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{[(3S)-1-(methoxyacetyl)piperidin-3-yl]oxy}quinazolin-4-amine

HATU (0.24 g) was added to a solution ofN-(3-chloro-2-fluorophenyl)-6-methoxy-7-[(3S)-piperidin-3-yloxy]quinazolin-4-aminedihydrochloride (250 mg), diisopropylethylamine (0.37 ml) andmethoxyacetic acid (0.054 g) in methylene chloride (9 ml) and themixture was stirred at room temperature for 2.5 hours. Methylenechloride (20 ml) was added and the organic layer was washed with aqueoussodium hydroxide (2M, 30 ml) and water (30 ml). The resulting productwas purified by flash column chromatography eluting with methanol (3%)and methylene chloride (97%) gave a foam. This was re-precipitated bystirring in diethyl ether (20 ml) to give the title product as a whitesolid (0.202 g); ¹H NMR Spectrum: (DMSO d₆373K) 1.60 (m, 1H), 1.88 (m,2H), 2.10 (m, 1H), 3.32 (s, 3H), 3.51 (m, 2H), 3.62 (m, 1H), 3.87 (m,1H), 3.98 (s, 3H), 4.02 (d, J=14 Hz, 1H), 4.12 (d, J=14 Hz, 1H), 4.66(m, 1H), 7.26 (m, 1H), 7.33 (s, 1H), 7.43 (m, 1H), 7.62 (m, 1H), 7.83(s, 1H), 8.40 (s, 1H), 9.34 (br s, 1H); Mass Spectrum: (M+H)⁺ 475.

TheN-(3-chloro-2-fluorophenyl)-6-methoxy-7-[(3S)-piperidin-3-yloxy]quinazolin-4-aminedihydrochloride used as starting material was prepared as follows:

Diethylazodicarboxylate (3.73 g) was added dropwise to a mixture oftert-butyl (3R)-3-hydroxypiperidine-1-carboxylate (4.29 g),4-chloro-6-methoxyquinazolin-7-ol (3.00 g) and triphenylphosphine (5.61g) in methylene chloride (75 ml). The solution was then heated to 40° C.and stirred for 3 hours. After cooling the mixture was filtered and thenpurified by flash column chromatography eluting withisohexane/acetone/triethylamine (80/20/1) to give tert-butyl(3S)-3-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]piperidine-1-carboxylateas a colourless oil (3.29 g) which was used directly; Mass Spectrum:(M+H)⁺ 394.

4.0M HCl in dioxane (6.0 ml) was added to a stirred suspension oftert-butyl(3S)-3-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]piperidine-1-carboxylate(3.21 g) and 3-chloro-2-fluoroaniline (0.98 ml) in acetonitrile (50 mL).The reaction mixture was heated at 80° C. and left at this temperatureovernight. The solvent was evaporated and the residue purified by flashcolumn chromatography eluting with increasingly polar mixtures ofmethylene chloride/7N ammonia solution in methanol (97/3 to 95/5) togiveN-(3-chloro-2-fluorophenyl)-6-methoxy-7-[(3S)-piperidin-3-yloxy]quinazolin-4-aminedihydrochloride as a solid (3.20 g); ¹H NMR Spectrum: (DMSO d₆) 1.56 (m,2H), 1.72 (m, 1H), 2.12 (m, 1H), 2.48-2.59 (m, 2H), 2.82 (m, 1H), 3.20(m, 1H), 3.95 (s, 3H), 4.49 (m, 1H), 7.26 (s, 1H), 7.28 (m, 1H), 7.47(m, 1H), 7.53 (m, 1H), 7.81 (s, 1H), 8.38 (s, 1H), 9.63 (s, 1H); MassSpectrum: (M+H)⁺ 403.

EXAMPLE 62-[(3S)-3-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2-oxoethanol

Using an analogous procedure to that described in Example5N-(3-chloro-2-fluorophenyl)-6-methoxy-7-[(3S)-piperidin-3-yloxy]quinazolin-4-aminedihydrochloride (250 mg) was coupled with glycolic acid (0.045 g). Theresulting product was purified by flash column chromatography elutingwith methanol (3%) and methylene chloride (97%) to give a foam. This wasre-precipitated by stirring in diethyl ether (20 ml) to give the titleproduct as a white solid (0.105 g); ¹H NMR Spectrum: (DMSO d₆373K) 1.59(m, 1H), 1.87 (m, 2H), 2.09 (m, 1H), 3.40-3.60 (m, 4H), 3.86 (m, 1H),3.98 (s, 3H), 4.04-4.18 (m, 2H), 4.66 (m, 1H), 7.24 (m, 1H), 7.31 (s,1H), 7.40 (m, 1H), 7.60 (m, 1H), 7.80 (s, 1H), 8.38 (s, 1H), 9.30 (br s,1H); Mass Spectrum: (M+H)⁺ 461.

EXAMPLE 7N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-({(3S)-1-[(4-methylpiperazin-1-yl)acetyl]piperidin-3-yl}oxy)quinazolin-4-amine

Chloroacetyl chloride (47 μl) was added to a solution ofN-(3-chloro-2-fluorophenyl)-6-methoxy-7-[(3S)-piperidin-3-yloxy]quinazolin-4-aminedihydrochloride (250 mg) and diisopropylethylamine (373 μl) in methylenechloride (10 ml) and the mixture was stirred at ambient temperature for1 hour. 1-Methylpiperazine (228 mg) was added, and the solution stirredfor 1 hour before being washed with aqueous sodium hydroxide (2M, 10 ml)and water (10 ml). The organics were then purified by flash columnchromatography eluting with methylene chloride/7N ammonia solution inmethanol (97/3) to give a foam. This was re-precipitated by stirring indiethyl ether (20 ml) to give the title product as a white solid (0.135g); ¹H NMR Spectrum: (DMSO d₆) 1.42-1.67 (m, 1H), 1.70-1.95 (m, 2H),1.98-2.48 (m, 9H), 2.18 (s, 3H), 2.82-3.05 (m, 1H), 3.20-4.02 (m, 8H),4.68 (m, 1H), 7.30 (m, 1H), 7.34 (s, 1H), 7.44-7.60 (m, 2H), 7.82 (m,1H), 8.38 (s, 1H), 9.64 (m, 1H); Mass Spectrum: (M+H)⁺ 543; meltingpoint 120 to 121° C.

EXAMPLE 8N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-({1-[(4-methylpiperazin-1-yl)acetyl]piperidin-4-yl}oxy)quinazolin-4-amine

Using an analogous procedure to that described in Example7N-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminedihydrochloride (250 mg) was reacted with chloroacetyl chloride (47 μl),followed by 1-Methylpiperazine (228 mg) and purification to give thetitle product as a white solid (0.110 g); ¹H NMR Spectrum: (DMSO d₆)1.57 (m, 1H), 1.72 (m, 1H), 1.96-2.12 (m, 2H), 2.15 (s, 3H), 2.27-2.48(m, 8H), 3.08-3.52 (m, 4H), 3.86-4.04 (m, 2H), 3.95 (s, 3H), 4.90 (m,1H), 7.30 (m, 1H), 7.37 (s, 1H), 7.47-7.58 (m, 2H), 7.83 (s, 1H), 8.38(s, 1H), 9.63 (s, 1H); Mass Spectrum: (M+H)⁺ 543.

EXAMPLE 9(2R)-1-[4-({4-[3-Chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol(Process (a))

A suspension of a hydrochloride salt ofN-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine(4.87 g, 11.1 mmol, prepared using an analogous process to thatdescribed in Example 1) in 1-methyl-2-pyrrolidinone (40 ml) was stirredand cooled in a bath of ice/water. Triethylamine (4.7 mls, 33.7 mmol),N,N-diisopropylethylamine (1.9 ml, 11 mmol) and D-(−)-lactic acid (1.5g, 16.7 mmol) were added. HATU (5.27 g, 13.87 mmol) was then addedportionwise such that the internal temperature remained less than 12° C.The reaction mixture was stirred at room temperature overnight andpartitioned between saturated aqueous sodium bicarbonate solution(NaHCO₃) and ethyl acetate (EtOAc). The combined organic layers werewashed with saturated aqueous ammonium chloride (×2), 50% aqueous brine(×2) and brine (×1), dried over anhydrous sodium sulfate, filtered andevaporated. The residues were purified by column chromatography elutingwith dichloromethane/7N ammonia in methanol (96/4). Fractions containingthe desired product were evaporated to a gum which was triturated withdiethylether/isohexane (1:1). This solid was then crystallised fromacetonitrile to give the title product as a white powder (2.93 g,55.6%); ¹H NMR Spectrum (DMSO d₆) 1.20 (d, 3H), 1.50-1.80 (m, 2H),1.93-2.13 (m, 2H), 3.15-3.53 (m, 2H), 3.94 (s, 3H), 3.72-4.08 (m, 2H),4.35-4.55 (m, 1H), 4.80-5.00 (m, 2H), 7.27 (dd, 1H); 7.34 (s, 1H);7.40-7.60 (m, 2H); 7.80 (s, 1H); 8.38 (s, 1H); 9.63 (s, 1H); MassSpectrum: (M+H)⁺ 475; melting point: 189 to 189.5° C.

EXAMPLE 10N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2R)-2-(methylamino)propanoyl]piperidin-4-yl}oxy)quinazolin-4-amine(Process (a))

tert-butyl{(1R)-2-[4-({4-[(3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-methyl-2-oxoethyl}methylcarbamate(2.22 g, 3.77 mmol) was dissolved in acetonitrile (20 ml) and treatedwith 4M HCl in dioxane (3.8 ml, 15.2 mmol) at 80° C. for 5 minutes. Thereaction mixture was partitioned between saturated aqueous sodiumhydrogen carbonate and ethyl acetate. The organics were washed withbrine (×1), dried over sodium sulfate, filtered and evaporated. Theresidues were purified by column chromatography eluting withdichloromethane/7N ammonia in methanol (92/8). Fractions containing thedesired product were evaporated to give a gum which was triturated withdiethyl ether/isohexane (1:1) to give the title product as a whitepowder. (1.55 g, 84.1%); ¹H NMR Spectrum: (DMSO d₆+CD₃CO₂D) 1.35 (d,3H), 1.61-1.81 (m, 2H), 1.98-2.15 (m, 2H), 2.48 (s, 3H), 3.26-3.51 (m,2H), 3.65-3.79 (m, 1H), 3.92 (s, 3H), 3.84-4.08 (m, 1H), 4.32-4.42 (m,1H), 4.85-4.99 (m, 1H), 7.20-7.29 (m, 1H), 7.36 (s, 1H), 7.42-7.54 (m,2H), 7.81 (s, 1H), 8.35 (s, 1H); Mass Spectrum: (M+H)⁺ 488.

The tert-butyl{(1R)-2-[4-({4-[(3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-methyl-2-oxoethyl}methylcarbamatestarting material was prepared as follows:

A hydrochloride salt ofN-(3-Chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine(2.0 g, 4.55 mmol) was coupled withN-tert-butoxycarbonyl-N-methyl-D-alanine according to the methoddescribed in Example 9. The product was purified using columnchromatography eluting with dichloromethane/7N ammonia in methanol(98/2) to give tert-butyl{(1R)-2-[4-({4-[(3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-methyl-2-oxoethyl}methylcarbamateas a foam. (2.34 g, 87.6%); ¹H NMR Spectrum: (CDCl₃) 1.29 (d, 3H),(1.48) (s, 9H), 1.75-1.89 (m, 1H), 1.89-2.04 (m, 2H), 2.07-2.22 (m, 1H),2.75 (s, 3H), 3.26-3.42 (m, 1H), 3.50-3.85 (m, 2H), 4.02 (s, 3H),3.91-4.28 (m, 1H), 4.65-4.93 (m, 1H), 5.10-5.21 (m, 1H), 7.05 (s, 1H),7.13-7.21 (m, 2H), 7.28-7.33 (m, 2H), 8.44-8.54 (m, 1H), 8.69 (s, 1H);Mass Spectrum: (M+H)⁺ 588

EXAMPLE 11N-(3-Chloro-2-fluorophenyl)-7-({1-[(2R)-2-(dimethylamino)propanoyl]piperidin-4-yl}oxy)-6-methoxyquinazolin-4-amine(Process (d))

A mixture ofN-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2R)-2-(methylamino)propanoyl]piperidin-4-yl}oxy)quinazolin-4-amine(0.5 g, 1.03 mmol (Example 10), paraformaldehyde (0.3 g, 10.0 mmol) andanhydrous magnesium sulfate (0.25 g, 2.08 mmol) in methanol (5 ml) wastreated with 4M hydrogen chloride in dioxane (257 μl, 1.03 mmol). Sodiumcyanoborohydride (0.26 g, 4.12 mmol) was added and the mixture heated to40° C. for 3 hours. The reaction mixture was then partitioned betweensaturated aqueous sodium hydrogen carbonate and ethyl acetate. Theorganics were washed with brine, dried over sodium sulfate, filtered andevaporated. The residue was purified by column chromatography elutingwith dichloromethane/7N ammonia in methanol (96/4). Fractions containingthe desired product were evaporated to give a gum which was trituratedwith diethyl ether/isohexane (1:1) to give the title product as a whitepowder (0.415 g, 80.7%); ¹H NMR Spectrum: (DMSO d₆+CD₃CO₂D) 1.18-1.25(m, 3H), 1.52-1.80 (m, 2H), 1.95-2.15 (m, 2H), 2.48 (s, 6H), 3.18-3.54(m, 2H), 3.73-3.91 (m, 1.5H), 3.92 (s, 3H), 4.00-4.14 (m, 1.5H),4.83-4.95 (m, 1H), 7.21-7.29 (m, 1H), 7.35 (s, 1H), 7.41-7.55 (m, 2H),7.80 (s, 1H), 8.35 (s, 1H); Mass Spectrum: (M+H)⁺ 502.

EXAMPLE 12N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2S)-2-methoxypropanoyl]piperidin-4-yl}oxy)quinazolin-4-amine(Process (a))

Solid TBTU (285 mg, 0.75 mmol) was added to a stirred solution ofN-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine(200 mg, 0.50 mmol), DIPEA (0.261 ml, 1.50 mmol) and(S)-(−)-2-methoxypropionic acid (57 mg, 0.55 mmol) in methylene chloride(3 ml). The resulting solution was allowed to stir at room temperatureovernight, diluted with methylene chloride (20 ml), washed with 2Nsodium hydroxide (2×5 ml), water (5 ml), dried (MgSO₄), filtered andevaporated. The resulting foams were purified using flash chromatographyon silica eluting with increasingly polar mixtures of methanol/methylenechloride (0/100-3/97) to give the title compound as a white solid(100%); ¹H NMR Spectrum: 1.34 (d, 3H), 1.64-1.72 (m, 2H), 2.04-2.07 (m,2H), 3.20 (s, 3H), 3.25-3.47 (m, 2H), 3.86-3.97 (m, 2H), 4.03 (s, 3H),4.21-4.23 (m, 1H), 4.88-4.91 (m, 1H), 7.28 (dd, 1H), 7.33 (s, 1H), 7.47(dd, 1H), 7.51 (dd, 1H), 7.92 (s, 1H), 8.38 (s, 1H), 9.67 (s, 1H); MassSpectrum: (M+H)⁺ 489.

TheN-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminestarting material was obtained from the corresponding dihydrochloridesalt (Example 1) by a basic aqueous work-up at pH=11.5 and extraction ofthe aqueous layer by dichloromethane. The organic layer was dried onmagnesium sulfate and concentrated to give the free amine as a whitefoam; ¹H NMR Spectrum: (CDCl₃) 1.78-1.85 (m, 2H+1NH), 2.18 (m, 2H), 2.80(m, 2H), 3.22 (m, 2H), 4.03 (s, 3H), 4.61 (m, 1H), 7.03 (s, 1H), 7.15(m, 2H), 7.29 (s, 1H), 7.31 (m, 1H), 8.50 (m, 1H), 8.69 (s, 1NH); MassSpectrum: (M+H)⁺ 403.

EXAMPLE 13N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2R)-2-methoxypropanoyl]piperidin-4-yl}oxy)quinazolin-4-amine(Process (a))

The method described in Example 12 was repeated using(R)-(+)-2-methoxypropionic acid (57 mg, 0.55 mmol) to give the titlecompound as a white solid (82%); ¹H NMR Spectrum: 1.24 (d, 3H),1.57-1.67 (m, 2H), 2.04-2.09 (m, 2H), 3.22 (s, 3H), 3.22-3.47 (m, 2H),3.87-3.97 (m, 2H), 3.97 (s, 3H), 4.22-4.27 (m, 1H), 4.92-4.95 (m, 1H),7.27-7.30 (dd, 1H), 7.35 (s, 1H), 7.47 (dd, 1H), 7.60 (dd, 1H), 7.82 (s,1H), 8.37 (s, 1H), 9.67 (s, 1H); Mass Spectrum: (M+H)⁺ 489.

EXAMPLE 14(2R)-2-Amino-3-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-3-oxopropan-1-ol(Process (a))

TBTU (709 mg, 1.87 mmol) was added to a stirred solution ofN-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine(500 mg, 1.24 mmol), DIPEA (0.648 ml, 3.72 mmol) andN-(tert-butoxycarbonyl)-D-serine (280 mg, 1.36 mmol) in methylenechloride (3 ml). The resulting solution was allowed to stir at roomtemperature overnight, diluted with methylene chloride (20 ml), washedwith 2N NaOH (2×5 ml), water (5 ml), dried (MgSO₄) and evaporated. Theresulting foam was dissolved in methylene chloride (5 ml) and treatedwith trifluoroacetic acid (5 ml). The resulting solution was left tostand at room temperature for 1 hour, concentrated and purified bymass-triggered preparative LCMS to give the title compound (42.5%); ¹HNMR Spectrum: 1.58-1.72 (m, 2H), 2.01-2.08 (m, 2H), 3.24-3.44 (m, 2H),3.80-4.03 (m, 4H), 3.95 (s, 3H), 4.77 (m, 1H), 4.91-4.94 (m, 1H), 7.27(dd, 1H), 7.35 (s, 1H), 7.47 (dd, 1H), 7.51 (dd, 1H), 7.82 (s, 1H), 8.38(s, 1H), 9.67 (s, 1H); Mass Spectrum: (M+H)⁺ 490.

EXAMPLE 15(2S)-2-Amino-3-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-3-oxopropan-1-ol

The method described in Example 14 was repeated but usingN-(tert-butoxycarbonyl)-L-serine (280 mg, 1.36 mmol) to give the titleproduct (32%); ¹H NMR Spectrum: 1.58-1.73 (m, 2H), 2.01-2.08 (m, 2H),3.24-3.44 (m, 2H), 3.80-4.00 (m, 4H), 3.97 (s, 3H), 4.74 (m, 1H),4.93-4.96 (m, 1H), 7.28 (dd, 1H), 7.35 (s, 1H), 7.47 (dd, 1H), 7.51 (dd,1H), 7.82 (s, 1H), 8.37 (s, 1H), 9.67 (s, 1H); Mass Spectrum: (M+H)⁺490.

EXAMPLE 16(2S)-3-[4-({4-[3-Chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2-(dimethylamino)-3-oxopropan-1-ol(Process(d))

Solid NaCNBH₃ (38.3 mg, 0.614 mmol) was added to a stirred solutionof(2S)-2-amino-3-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-3-oxopropan-1-ol(150 mg, 0.307 mmol, Example 15), sodium acetate trihydrate (251 mg,3.07 mmol), formaldehyde 37% (aq) (2.5 ml) and acetic acid (184 mg, 3.07mmol) at 0-5° C. The resulting solution was allowed to warm to roomtemperature and stir for 1 hour. The mixture was then evaporated and theresulting yellow residue was purified by flash chromatography on silicagel eluting with increasingly polar mixtures of dichloromethane/7Nammonia in methanol (100/0-85/15). Fractions containing the desiredproduct were combined and evaporated to give the title compound as awhite solid (26%); ¹H NMR Spectrum: 1.52-1.69 (m, 2H), 1.94-2.07 (m,2H), 2.28-2.30 (2×s, 6H), 3.15-3.22 (m, 2H), 3.53-3.76 (m, 4H), 3.94 (s,3H), 4.02 (m, 1H), 4.49 (m, 1H), 4.92-4.94 (m, 1H), 7.27 (dd, 1H), 7.34(s, 1H), 7.47 (dd, 1H), 7.51 (dd, 1H), 7.81 (s, 1H), 8.38 (s, 1H), 9.65(s, 1H); Mass Spectrum: (M+H)⁺ 518.

EXAMPLE 17(2R)-3-[4-({4-[3-Chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2-(dimethylamino)-3-oxopropan-1-ol(Process(d))

The process described in Example 16 was repeated using(2R)-2-amino-3-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-3-oxopropan-1-ol(150 mg, 0.307 mmol, Example 14) to give the title compound (32%); ¹HNMR Spectrum: 1.58-1.69 (m, 2H), 1.93-2.06 (m, 2H), 2.26-2.28 (2×s, 6H),3.17-3.20 (m, 2H), 3.53-3.74 (m, 4H), 3.94 (s, 3H), 4.04 (m, 1H), 4.47(m, 1H), 4.91 (m, 1H), 7.26 (dd, 1H), 7.35 (s, 1H), 7.47 (dd, 1H), 7.51(dd, 1H), 7.81 (s, 1H), 8.37 (s, 1H), 9.66 (s, 1H); Mass Spectrum:(M+H)⁺ 518.

EXAMPLE 18(2S)-1-(4-{[4-[3-Chloro-2-fluoroanilino]-6-(2-pyrrolidin-1-ylethoxy)quinazolin-7-yl]oxy}piperidin-1-yl)-1-oxopropan-2-ol(Process (b))

(S)-(−)-2-Acetoxyproprionyl chloride (0.131 g, 0.87 mmol) was added to astirred solution ofN-(3-chloro-2-fluorophenyl)-7-(piperidin-4-yloxy)-6-(2-pyrrolidin-1-ylethoxy)quinazolin-4-aminetrihydrochloride (220 mg, 0.395 mmol) and triethylamine (0.110 ml, 0.79mmol) in methylene chloride (10 ml) at −10° C. The resulting solutionwas allowed to warm to room temperature and stirred for 30 minutes. Theresulting yellow solution was diluted with methylene chloride (10 ml)and washed with water (3×5 ml), dried (MgSO₄) and evaporated. Theresulting foam was dissolved in THF (1 ml) and pyrrolidine (1 ml) wasadded. The mixture was heated at 70° C. for 3 hours, evaporated and theresidues purified by flash chromatography on silica gel eluting withdichloromethane/7N ammonia in methanol (95/5). Fractions containing thedesired product were combined and evaporated to give the title productas a white solid. (0.099 g, 45.6%); ¹H NMR Spectrum: (DMSO-d₆): δ 1.20(d, 3H), 1.52-1.82 (m, 6H), 1.86-2.08 (m, 4H), 3.24-3.50 (m, 4H),3.74-3.86 (m, 2H), 4.28 (m, 2H), 4.45 (m, 1H), 4.89-4.95 (m, 3H), 7.27(dd, 1H), 7.36 (s, 1H), 7.48 (dd, 1H), 7.53 (dd, 1H), 7.87 (s, 1H), 8.38(s, 1H), 9.65 (s, 1H); Mass Spectrum: (M+H)⁺ 558.

TheN-(3-chloro-2-fluorophenyl)-7-(piperidin-4-yloxy)-6-(2-pyrrolidin-1-ylethoxy)quinazolin-4-aminetrihydrochloride used as a starting material (1) was prepared asfollows:

1,2-Dichloroethane (5 ml) was added to a stirred suspension of4-(3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline 6 (2.0 g,6.27 mmol, prepared as described in Reference Example 2 of WO03/08283 1)and potassium carbonate (1.39 g, 10.0 mmol) in DMF (10 ml), and theresulting suspension was heated at 60° C. for 48 hours. The reactionmixture was diluted with methylene chloride (50 ml) and washed withwater (3×20 ml), dried (MgSO₄) and evaporated to dryness to afford 5(2.39 g, 100%) as a brown oil which was used without furtherpurification; Mass Spectrum: (M+H)⁺ 382.

Pyrrolidine (4.44 g, 5.13 ml, 62.5 mmol) was added to a stirred solutionof 5 (2.38 g, 6.25 mmol) in DMF (30 ml) and the resulting pale brownsolution was heated at 90° C. for 2 hours. The reaction mixture wasevaporated to dryness using a rotary evaporator and under high vacuum toafford 4 (2.6 g, 100%) as a brown foam; Mass Spectrum: (M+H)⁺ 417.

Intermediate 4 (2.60 g, 6.3 mmol) was added to neat liquid pyridiniumhydrochloride (3.6 g, 31.3 mmol) at 170° C. over a period of 5 minutes.The reaction mixture was allowed to stir at 170° C. for 1 hour. Thereaction mixture was cooled to room temperature and the resulting solidwas suspended in water (30 ml) and the resulting black precipitateeliminated by filtration. The pH of the filtrate was increased to 7 withconcentrated aqueous ammonia and the resulting solution was evaporatedto dryness. The resulting beige solid was purified by flashchromatography on silica gel eluting with increasingly polar mixtures ofdichloromethane/7N ammonia in methanol (100/0-85/15). Fractionscontaining the desired product were combined and evaporated to give 3 asa pale green foam (1.62 g, 64%). Mass Spectrum: (M+H)⁺ 403.

Di-tert-butylazodicarboxylate (0.571 g, 2.48 mmol) was added to astirred solution of 3 (500 mg, 1.24 mmol),4-hydroxy-1-tert-butoxycarbonylpiperidine (374 mg, 1.86 mmol) andtriphenylphosphine (660 mg, 2.48 mmol) in THF (10 ml) at 0° C. over 5minutes. The resulting yellow solution was allowed to warm to roomtemperature and subsequently heated at 70° C. for 1 hour. The reactionmixture was concentrated and the residues were purified by flashchromatography on silica gel eluting with increasingly polar mixtures ofmethylene chloride/7N ammonia in methanol (100/0-95/5). Fractionscontaining the desired product were combined and evaporated to give a 2as a pale green oil (0.52 g, 72%); Mass Spectrum: (M+H)⁺ 586.

TFA (1 ml) was added to a stirred solution of 2 (220 mg, 0.395 mmol) inmethylene chloride (1 ml) at 0° C. over 5 minutes. The resulting yellowsolution was allowed to warm to room temperature and stir for 1 hour.The reaction mixture was evaporated to dryness and the residuesre-dissolved in methylene chloride (10 ml). Ethyl ether (10 ml) wasadded followed by a 4.0 M solution of HCl in dioxane (2 ml). Theresulting thick white precipitate was collected by filtration, washedwith Ethyl ether (3×2 ml) and dried to a constant weight to giveN-(3-chloro-2-fluorophenyl)-7-(piperidin-4-yloxy)-6-(2-pyrrolidin-1-ylethoxy)quinazolin-4-aminetrihydrochloride (1) as a white solid which was used without furtherpurification (0.48 g, 100%); Mass Spectrum: (M+H)⁺ 486.

EXAMPLE 19(2S)-1-(4-{[4-[3-Chloro-2-fluoroanilino]-6-(2-methoxyethoxy)quinazolin-7-yl]oxy}piperidin-1-yl)-1-oxopropan-2-ol(Process (a))

TBTU (200 mg, 0.525 mmol) was added to a stirred solution ofN-(3-chloro-2-fluorophenyl)-6-(2-methoxyethoxy)-7-(piperidin-4-yloxy)quinazolin-4-aminedihydrochloride (180 mg, 0.404 mmol), L-(+)-lactic acid (37 mg, 0.44mmol) and DIPEA (0.091 ml, 0.525 mmol) in methylene chloride (10 ml).The resulting solution was stirred at room temperature for 2 hours thendiluted with methylene chloride (10 ml). This solution was washed with2N NaOH (2×5 ml), dried (MgSO₄), filtered and evaporated. The residueswere purified by flash chromatography on silica gel eluting withmethylene chloride/7N ammonia in methanol (95/5) to give the titleproduct as a white solid (89 mg, 42.6%); ¹H NMR Spectrum: (DMSO-d₆): δ1.21 (d, 3H), 1.64-1.72 (m, 2H), 1.86-2.07 (m, 2H), 3.37-3.46 (m, 2H),3.77-3.92 (m, 5H), 4.27 (m, 2H), 4.46 (m, 1H), 4.90-4.92 (m, 3H), 7.29(dd, 1H), 7.36 (s, 1H), 7.48 (dd, 1H), 7.52 (dd, 1H), 7.86 (s, 1H), 8.38(s, 1H), 9.63 (s, 1H); Mass Spectrum: (M+H)⁺ 519.

TheN-(3-chloro-2-fluorophenyl)-6-(2-methoxyethoxy)-7-(piperidin-4-yloxy)quinazolin-4-aminedihydrochloride (intermediate 7 in the reaction scheme below) used asstarting material was prepared as follows:

Solid 4-(3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline 6(1.00 g, 3.13 mmol) was added to neat liquid pyridinium hydrochloride(3.62 g, 31.3 mmol) at 170° C. over a period of 10 minutes. The reactionmixture was stirred at 170° C. for 2 hours then cooled to roomtemperature. The mixture was then suspended in water (30 ml) and theresulting precipitate was collected by filtration, washed withacetonitrile (5 ml) diethyl ether (5 ml) and dried to a constant weightin a vacuum oven at 50° C. to afford 10 as a beige solid (0.71 g, 77%);Mass Spectrum: (M+H)⁺ 306.

Acetic anhydride (117 mg, 1.15 mmol) and a solution NaOH (46 mg, 1.15mmol) in water (3 ml) was added to a stirred suspension of 10 (350 mg,1.15 mmol) in THF (3 ml) at −10° C. The resulting two-phase mixture wasstirred at room temperature for 2 hours. The organic phase was retained,dried (MgSO₄) and evaporated to dryness. The resulting beige foam wastriturated with acetonitrile (3 ml), cooled to 0° C. and the resultingprecipitate was collected by filtration and dried to a constant weightat 40° C. in a vacuum oven to give 9 as a beige solid (232 mg, 68%);Mass Spectrum: (M+H)⁺ 348.

Solid di-tert-butylazodicarboxylate (364 mg, 1.58 mmol) was added to astirred solution of 9 (250 mg, 0.72 mmol), triphenylphosphine (420 mg,1.58 mmol) and 4-hydroxy-1-tert-butoxycarbonylpiperidine (289 mg, 1.44mmol) in THF (10 ml) at room temperature over 5 minutes. The resultingyellow solution was stirred at room temperature for 2 hours andconcentrated to afford a yellow foam. The foam was dissolved in 7N NH₃in MeOH (5 ml) and left to stand for 1 hour. The solution wasconcentrated and purified by flash chromatography on silica gel (elutionwith a mixture of DCM-MeOH 95/5) to give 8 (138 mg, 39%) as a beigefoam; Mass Spectrum: (M+H)⁺ 489.

Solid di-tert-butylazodicarboxylate (166 mg, 0.72 mmol) was added to astirred solution of 8 (115 mg, 0.24 mmol), triphenylphosphine (0.191 g,0.72 mmol) and 2-methoxyethanol (55 mg, 0.72 mmol) in THF (2 ml) at roomtemperature over 5 minutes. The resulting yellow solution was stirred atroom temperature for 2 hours then concentrated to a yellow foam. Thiswas dissolved in DCM (1 ml), treated with trifluoroacetic acid (1 ml)and left to stand for 1 hour. The solution was concentrated and purifiedby mass-triggered preparative LCMS to giveN-(3-chloro-2-fluorophenyl)-6-(2-methoxyethoxy)-7-(piperidin-4-yloxy)quinazolin-4-aminedihydrochloride (7) as a white solid (80 mg, 77%); Mass Spectrum: (M+H)⁺447.13.

EXAMPLE 204-[3-chloro-2-fluoroanilino]-7-({1-[(2S)-2-hydroxypropanoyl]piperidin-4-yl}oxy)quinazolin-6-ol

Solid lithium iodide (2.11 g, 15.8 mmol) was added to stirred neat2,4,6-collidine (5 ml) at 130° C. The resulting yellow solution washeated at 130° C. for 1 hour. Solid(2S)-1-[4-({4-[(3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol(1.5 g, 3.17 mmol, Example 4[5]) over a period of 10 minutes. Theresulting solution was stirred at 130° C. for 16 hours to give a darkbrown solid precipitate. The liquid was decanted and the solid waspurified by mass-triggered preparative LCMS to give the title product asa brown solid (1.30 g, 87%); ¹H NMR Spectrum: (DMSO-d₆): δ1.21 (d, 3H),1.61-1.77 (m, 2H), 1.95-2.08 (m, 2H), 3.41-3.51 (m, 2H), 3.86-3.92 (m,2H), 4.47 (m, 1H), 4.91 (m, 1H), 7.26 (m, 1H), 7.32 (s, 1H), 7.45 (m,1H), 7.53 (m, 1H), 7.70 (s, 1H), 8.33 (s, 1H), 9.45 (s, 2H); MassSpectrum: (M+H)⁺ 461.

EXAMPLE 21(2S)-1-[4-({4-[3-Chloro-2-fluoroanilino]-6-isopropoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol(Process (f))

Solid di-tert-butylazodicarboxylate (225 mg, 0.98 mmol) was added to astirred solution of 2-propanol (0.074 ml, 0.98 mmol) andtriphenylphosphine (260 mg, 0.98 mmol) in THF (1 ml) at 0° C. over 5minutes. The resulting yellow solution was allowed to warm to roomtemperature and4-[3-chloro-2-fluoroanilino]-7-({1-[(2S)-2-hydroxypropanoyl]piperidin-4-yl}oxy)quinazolin-6-ol(250 mg, 0.33 mmol, Example 20) was added. The mixture was heated at 80°C. for 3 hours, cooled and evaporated. The residues were purified bymass-triggered preparative LCMS to give the title compound as a whitesolid (75 mg, 45.7%); ¹H NMR Spectrum: (CDCl₃): δ 1.37 (d, 3H), 1.43 (d,6H), 1.61-1.72 (m, 2H), 1.95-2.07 (m, 2H), 3.38-3.50 (m, 2H), 3.78-3.88(m, 2H), 4.49 (m, 1H), 4.66 (m, 1H), 4.82 (m, 1H), 7.15 (m, 3H), 7.31(s, 1H), 8.52 (s, 1H), 8.69 (s, 1H); Mass Spectrum: (M+H)⁺ 503.

EXAMPLE 22(2S)-1-[4-({4-[(3-Chloro-4-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol(Process (a))

HATU (190 mg, 0.5 mmol) was added to a stirred solution ofN-(3-chloro-4-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminehydrochloride (200 mg, 0.456 mmol), L-(+)-lactic acid (45 mg, 0.5 mmol)and N-methyl morpholine (0.15 ml, 1.39 mmol) in DMF (10 ml) at roomtemperature. After 2 hours the mixture was evaporated to dryness and theresidues were purified by column chromatography on silica eluting withincreasingly polar mixtures of dichloromethane/methanol (99/1-90/10).Fractions containing the desired product were evaporated to a gum. Thiswas triturated with diethylether (10 ml) and the resulting solid wascollected by filtration and dried under high vacuum to give the titleproduct as a white powder. (54.2 mg, 25%); ¹H NMR Spectrum: (DMSO d₆)1.1-1.3 (m, 3H), 1.5-1.8 (m, 2H), 1.9-2.15 (m, 2H), 3.0-3.60 (m, 2H+H₂O), 3.7-4.1 (m, 2H), 3.95 (s, 3H), 4.43 (m, 1H), 4.95 (m, 2H), 7.32(s, 1H), 7.47 (dd, 1H), 7.7-7.8 (m, 1H), 7.83 (s, 1H), 8.0-8.1 (m, 1H),8.58 (s, 1H), 9.87 (bs, 1H); Mass Spectrum: (M+H)⁺ 475.

TheN-(3-chloro-4-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminehydrochloride used as the starting material was prepared as follows:

Di-tert-butylazodicarboxylate (1.64 g, 7.14 mmol) in methylene chloride(20 ml) was added slowly to a stirred suspension of4-Chloro-6-methoxyquinazolin-7-ol (1.0 g, 4.76 mmol, prepared asdescribed in WO2004041829, Example 1 therein (preparation of startingmaterials)), 4-hydroxy-1-tert-butoxycarbonylpiperidine (1.44 g, 7.14mmol) and triphenylphosphine (1.87 g, 7.14 mmol) in methylene chloride(50 ml) at 5° C. under an atmosphere of nitrogen. The reaction mixturewas allowed to warm to room temperature for 18 hours. The reactionmixture was then filtered and purified by flash chromatography on silicaeluting with increasingly polar mixtures of isohexane/ethylacetate/triethylamine (75/24/1 followed by 0/99/1). The fractionscontaining the desired product were combined and evaporated under vacuumto give tert-butyl4-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]piperidine-1-carboxylate as awhite solid (1.75 g, 93.4%); ¹H NMR Spectrum: (DMSO d₆) 1.40 (s, 9H),1.5-1.7 (m, 2H), 1.9-2.1 (m, 2H), 3.1-3.3 (m, 2H), 3.60-3.80 (m, 2H),3.95 (s, 3H), 4.92 (m, 1H), 7.38 (s, 1H), 7.58 (s, 1H), 8.83 (s, 1H);Mass Spectrum: (M+H)⁺ 394.

4.0M HCl in Dioxane (1 ml) was added to a suspension of tert-butyl4-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]piperidine-1-carboxylate (331mg, 0.84 mmol) and 3-chloro-4-fluoroaniline (134.5 mg) in acetonitrile(10 ml). The reaction mixture was stirred and heated at 70° C. for 4hours. The resulting precipitate was filtered hot, washed withacetonitrile and dried under vacuum to giveN-(3-chloro-4-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminehydrochloride (566 mg); Mass Spectrum: (M+H)⁺ 403.

EXAMPLE 23(2R)-1-[4-({4-[3-Chloro-4-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol(Process (a))

D-Lactic acid was coupled withN-(3-chloro-4-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminehydrochloride using the same conditions as those described in Example 22to give the title product; ¹H NMR Spectrum: (DMSO d₆) 1.2 (d, 3H),1.5-1.8 (m, 2H), 1.9-2.15 (m, 2H), 3.1-3.50 (m, 2H+ H₂O), 3.7-4.1 (m,2H), 3.95 (s, 3H), 4.45 (pent, 1H), 4.8-5.8 (m, 2H), 7.32 (s, 1H), 7.45(dd, 1H), 7.7-7.85 (m, 2H), 8.1 (dd, 1H), 8.5 (s, 1H), 9.55 (s, 1H);Mass Spectrum: (M+H)⁺ 475; melting point 143.6° C.

EXAMPLE 24(2S)-1-[4-({4-[3-Bromoanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol(Process (a))

N-(3-Bromophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminehydrochloride was coupled with L-(+)-lactic acid using an analogousprocess to that described in Example 22 to give the title product as awhite powder; ¹H NMR Spectrum: (DMSO d₆) 1.2 (d, 3H), 1.5-1.8 (m, 2H),1.9-2.15 (m, 2H), 3.1-3.60 (m, 2H+ H₂O), 3.7-4.1 (m, 2H), 3.95 (s, 3H),4.45 (m, 1H), 4.8-5.0 (m, 2H), 7.2-7.4 (m, 3H), 7.8-7.9 (m, 2H), 8.13(s, 1H), 8.5 (s, 1H), 9.5 (s, 1H); Mass Spectrum: (M+H)⁺ 501, 503.

The N-(3-bromophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine

hydrochloride starting material was prepared as follows.

tert-Butyl4-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]piperidine-1-carboxylate wascoupled with 3-bromoaniline using an analogous process to that describedin Example 21 (preparation of starting materials) for the preparation ofN-(3-chloro-4-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminehydrochloride, to giveN-(3-bromophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminehydrochloride; ¹H NMR Spectrum: (DMSO d₆): 1.8-2.1 (m, 2H), 2.1-2.3 (m,2H), 3.0-3.35 (m, 4H), 4.05 (s, 3H), 4.88 (m, 1H), 7.38-7.52 (m, 2H),7.6 (s, 1H), 7.8 (d, 1H), 8.05 (s, 1H), 8.5 (s, 1H), 8.87 (s, 1H), 9.2(bs, 2H), 11.7 (s, 1H); Mass Spectrum: (M+H)⁺ 431.

EXAMPLE 25(2R)-1-[4-({4-[3-Bromoanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol

N-(3-bromophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminehydrochloride was coupled with D-lactic acid using an analogous processto that described in Example 22 to give the title product as a whitepowder; ¹H NMR Spectrum: (DMSO d₆) 1.2 (d, 3H), 1.5-1.8 (m, 2H),1.9-2.15 (m, 2H), 3.1-3.55 (m, 2H+ H₂O), 3.7-4.1 (m, 2H), 3.95 (s, 3H),4.43 (m, 1H), 4.8-5.0 (m, 2H), 7.2-7.4 (m, 3H), 7.8-7.9 (m, 2H), 8.15(s, 1H), 8.5 (s, 1H), 9.5 (s, 1H); Mass Spectrum: (M+H)⁺ 501, 503.

EXAMPLE 26(2S)-1-[4-({4-[5-Chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol(Process (a))

N-(5-Chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminehydrochloride was coupled with L-(+)-lactic acid using an analogousprocess to that described in Example 22 to give the title product as awhite powder; ¹H NMR Spectrum: (DMSO d₆) 1.2 (d, 3H), 1.5-1.8 (m, 2H),1.9-2.15 (m, 2H), 3.1-3.60 (m, 2H+ H₂O), 3.7-4.1 (m, 2H), 3.95 (s, 3H),4.45 (m, 1H), 4.8-5.0 (m, 2H), 7.3-7.45 (m, 3H), 7.7 (d, 1H), 7.85 (s,1H), 8.5 (s, 1H), 9.95 (s, 1H); Mass Spectrum: (M+H)⁺ 475.

TheN-(5-Chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminehydrochloride starting material was prepared as follows.

tert-butyl4-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]piperidine-1-carboxylate wascoupled with 2-fluoro-5-chloroaniline using an analogous process to thatdescribed in Example 22 (preparation of starting materials) for thepreparation ofN-(3-chloro-4-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminehydrochloride, to giveN-(5-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminehydrochloride;

¹H NMR Spectrum: (DMSO d₆) 1.8-2.1 (m, 2H), 2.1-2.35 (m, 2H), 3.0-3.35(m, 4H), 4.05 (s, 3H), 4.8-5.0 (m, 1H), 7.4-7.55 (m, 2H), 7.55-7.75 (m,2H), 8.45 (s, 1H), 8.82 (s, 1H), 9.22 (bs, 2H), 11.94 (s, 1H); MassSpectrum: (M+H)⁺ 403.

EXAMPLE 27(2R)-1-[4-({4-[5-Chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol(Process (a))

N-(5-Chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminehydrochloride was coupled with D-lactic acid using an analogous processto that described in Example 22 to give the title product as a whitepowder; ¹H NMR Spectrum: (DMSO d₆) 1.2 (d, 3H), 1.45-1.8 (m, 2H),1.9-2.15 (m, 2H), 3.1-3.55 (m, 2H+ H₂O), 3.7-4.1 (m, 2H), 3.95 (s, 3H),4.45 (pent, 1H), 4.8-5.0 (m, 2H), 7.25-7.45 (m, 3H), 7.7 (dd, 1H), 7.8(s, 1H), 8.4 (s, 1H), 9.55 (s, 1H); Mass Spectrum: (M+H)⁺ 475.

EXAMPLE 28(2S)-1-[4-({4-[3-Ethynylanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol(Process (a))

N-(3-Ethynylphenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminehydrochloride was coupled with L-(+)-lactic acid using an analogousprocess to that described in Example 22 to give the title product as awhite powder; ¹H NMR Spectrum: (DMSO d₆) 1.2 (d, 3H), 1.45-1.8 (m, 2H),1.9-2.15 (m, 2H), 3.1-3.55 (m, 2H+ H₂O), 3.7-4.1 (m, 2H), 3.95 (s, 3H),4.18 (s, 1H), 4.45 (pent, 1H), 4.8-5.0 (m, 2H), 7.2 (d, 1H), 7.33 (s,1H), 7.39 (dd, 1H), 7.83 (s, 1H), 7.89 (d, 1H), 7.97 (s, 1H), 8.5 (s,1H), 9.48 (s, 1H); Mass Spectrum: (M+H)⁺ 447.

TheN-(3-ethynylphenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminehydrochloride used as starting material was prepared as follows:

tert-butyl4-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]piperidine-1-carboxylate wascoupled with 3-ethynylaniline using an analogous process to thatdescribed in Example 22 (preparation of starting materials) for thepreparation ofN-(3-chloro-4-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminehydrochloride, to giveN-(3-ethynylphenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminehydrochloride ¹H NMR Spectrum: (DMSO d₆) 1.85-2.1 (m, 2H), 2.1-2.3 (m,2H), 3.0-3.35 (m, 4H), 4.05 (s, 3H), 4.25 (s, 1H), 4.8-4.95 (m, 1H),7.39 (d, 1H), 7.47 (dd, 1H), 7.6 (s, 1H), 7.8 (d, 1H), 7.89 (s, 1H), 8.5(s, 1H), 8.83 (s, 1H), 9.22 (bs, 2H), 11.68 (s, 1H); Mass Spectrum:(M+H)⁺ 375.

EXAMPLE 29(2R)-1-[4-({4-[(3-Ethynylanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol(Process (a))

N-(3-Ethynylphenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminehydrochloride was coupled with D-lactic acid using an analogous processto that described in Example 28 to give the title product as a whitepowder; ¹H NMR Spectrum: (DMSO d₆) 1.2 (d, 3H), 1.45-1.8 (m, 2H),1.9-2.15 (m, 2H), 3.1-3.55 (m, 2H+ H₂O), 3.7-4.1 (m, 2H), 3.95 (s, 3H),4.18 (s, 1H), 4.45 (pent, 1H), 4.8-5.0 (m, 2H), 7.2 (d, 1H), 7.33 (s,1H), 7.39 (dd, 1H), 7.83 (s, 1H), 7.89 (d, 1H), 7.97 (s, 1H), 8.48 (s,1H), 9.47 (s, 1H); Mass Spectrum: (M+H)⁺ 447.

EXAMPLE 30(2S)-1-[4-({4-[3-Bromo-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol(Process (a))

N-(3-Bromo-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminehydrochloride was coupled with L-(+)-lactic acid using an analogousprocess to that described in Example 22 to give the title product as awhite powder; ¹H NMR Spectrum: (DMSO d₆) 1.2 (d, 3H), 1.45-1.8 (m, 2H),1.9-2.15 (m, 2H), 3.1-3.55 (m, 2H+ H₂O), 3.7-4.1 (m, 2H), 3.95 (s, 3H),4.45 (pent, 1H), 4.8-5.0 (m, 2H), 7.21 (dd, 1H), 7.32 (s, 1H), 7.48-7.65(m, 2H), 7.8 (s, 1H), 8.37 (s, 1H), 9.6 (s, 1H); Mass Spectrum: (M+H)⁺521.

TheN-(3-Bromo-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminehydrochloride starting material was prepared as follows:

tert-Butyl4-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]piperidine-1-carboxylate wascoupled with tert-butyl (3-bromo-2-fluorophenyl)carbamate using ananalogous process to that described in Example 22 (preparation ofstarting materials) for the preparation ofN-(3-chloro-4-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminehydrochloride, to giveN-(3-bromo-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminehydrochloride; ¹H NMR Spectrum: (DMSO d₆) 1.85-2.1 (m, 2H), 2.1-2.32 (m,2H), 3.0-3.35 (m, 4H), 4.02 (s, 3H), 4.83-5.0 (m, 1H), 7.3 (dd, 1H),7.5-7.65 (m, 2H), 7.75 (dd, 1H), 8.45 (s, 1H), 8.8 (s, 1H), 9.15 (bs,2H), 11.86 (s, 1H); Mass Spectrum: (M+H)⁺ 447.12.

The tert-butyl (3-bromo-2-fluorophenyl)carbamate starting material wasprepared as follows. Triethylamine (0.6 ml) was added to a stirredsolution of 3-bromo-2-fluorobenzoic acid (438 mg, 2 mmol) intert-butanol (10 ml). Diphenyl phosphoryl azide (1 ml, 4.6 mmol) wasthen added and the reaction mixture was heated under reflux overnight.

The solution was evaporated to dryness and azeotroped with toluene. Theresidues were then purified by flash chromatography on silica elutingwith ethyl acetate/1-hexane (10/90). Fractions containing the requiredproduct were combined and evaporated to give tert-butyl(3-bromo-2-fluorophenyl)carbamate as a white solid (330 mg); ¹H NMRSpectrum: (CDCl₃) 1.5 (s, 9H), 6.4 (s, 1H), 7.1-7.25 (m, 1H), 7.7 (dd,1H).

EXAMPLE 31(2R)-1-[4-({4-[3-Bromo-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol(Process (a))

N-(3-Bromo-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminehydrochloride was coupled with D-lactic acid using an analogous processto that described in Example 22 to give the title product as a whitepowder; ¹H NMR Spectrum: (DMSO d₆) 1.2 (d, 3H), 1.45-1.8 (m, 2H),1.9-2.15 (m, 2H), 3.1-3.55 (m, 2H+ H₂O), 3.7-4.1 (m, 2H), 3.95 (s, 3H),4.45 (pent, 1H), 4.8-5.0 (m, 2H), 7.22 (dd, 1H), 7.32 (s, 1H), 7.48-7.65(m, 2H), 7.8 (s, 1H), 8.37 (s, 1H), 9.62 (s, 1H); Mass Spectrum: (M+H)⁺521.

EXAMPLE 32(2S)-1-[4-({4-[(4-Chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol(Process (a))

N-(4-Chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminehydrochloride was coupled with L-(+)-lactic acid using an analogousprocess to that described in Example 22 to give the title product as awhite powder; ¹H NMR Spectrum: (DMSO d₆) 1.2 (d, 3H), 1.45-1.8 (m, 2H),1.9-2.15 (m, 2H), 3.1-3.55 (m, 2H+ H₂O), 3.7-4.1 (m, 2H), 3.93 (s, 3H),4.44 (pent, 1H), 4.8-5.0 (m, 2H), 7.25-7.4 (m, 2H), 7.45-7.65 (m, 2H),7.8 (s, 1H), 8.33 (s, 1H), 9.5 (s, 1H); Mass Spectrum: (M+H)⁺ 475;melting point 149° C.

TheN-(4-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminehydrochloride starting material was prepared as follows:

4-[(4-chloro-2-fluorophenyl)amino]-6-methoxyquinazolin-7-ol (5 g, 15.65mmol, prepared as described in WO 2001/077085) was dissolved in DMA (200ml). tert-Butyl (4-methanesulfonyloxy)piperidine-1-carboxylate (6.55 g,23.5 mmol) and cesium fluoride (7.09 g, 46.95 mmol) were added, and themixture was heated to 60° C. with stirring. The solvent was evaporated,and the residue was partitioned between water (200 ml) and EtOAc (200ml). The organics were washed with water (2×100 ml) and brine (100 ml),dried over MgSO₄ and evaporated to give tert-butyl4-({4-[4-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidine-1-carboxylate(7.23 g, 91.9%); ¹H NMR Spectrum: (DMSO-d₆): 1.4 (d, 9H), 1.5-1.7 (m,2H), 1.8-2.1 (m, 2H), 3.1-3.3 (m, 2H), 3.65-3.85 (m, 2H), 3.91 (s, 3H),4.75-4.9 (m, 1H), 7.3 (s, 1H), 7.32 (dd, 1H), 7.54 (dd, 1H), 7.57 (dd,1H), 7.80 (s, 1H), 8.32 (s, 1H), 9.5 (s, 1H); Mass Spectrum: (M+H)⁺ 503.

A solution of 4M hydrogen chloride in dioxane (100 ml) was added to astirred solution of tert-butyl4-({4-[4-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidine-1-carboxylate(7.23 g, 14.4 mmol) in acetonitrile (100 ml). The reaction mixture washeated at 70° C. for 1 hour then concentrated to ½ volume. The resultingprecipitate was collected by filtration, washed with acetonitrile anddried under vacuum to giveN-(4-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminehydrochloride as a white solid (4.42 g, 76.3%); ¹H NMR Spectrum:(DMSO-d₆): 1.90-2.10 (m, 2H), 2.10-2.32 (m, 2H), 3.00-3.35 (m, 4H), 4.02(s, 3H), 4.90 (m, 1H), 7.36-7.50 (m, 1H), 7.50-7.70 (m, 3H), 8.48 (s,1H), 8.80 (s, 1H), 9.30 (bs, 2H), 11.90 (bs, 1H); Mass Spectrum: (M+H)⁺403.

EXAMPLE 33(2R)-1-[4-({4-[4-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol(Process)a))

N-(4-Chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminehydrochloride was coupled with D-lactic acid using an analogous processto that described in Example 22 to give the title product as a whitepowder; ¹H NMR Spectrum: (DMSO d₆) 1.2 (d, 3H), 1.45-1.8 (m, 2H),1.9-2.15 (m, 2H), 3.1-3.55 (m, 2H+ H₂O), 3.7-4.1 (m, 2H), 3.93 (s, 3H),4.43 (pent, 1H), 4.80-4.98 (m, 2H), 7.25-7.4 (m, 2H), 7.45-7.65 (m, 2H),7.8 (s, 1H), 8.35 (s, 1H), 9.5 (s, 1H); Mass Spectrum: (M+H)⁺ 475;melting point 118° C.

EXAMPLE 34N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{[1-(1-methyl-L-prolyl)piperidin-4-yl]oxy}quinazolin-4-amine(Process)a))

N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminehydrochloride was coupled with N-methyl-L-proline using an analogousprocess to that described in Example 2 to give the title product as awhite powder; ¹H NMR Spectrum: (DMSO d₆) 1.4-1.9 (m, 5H), 1.9-2.20 (m,7H), 2.9-3.05 (m, 1H), 3.05-3.25 (m, 2H), 3.25-3.65 (m, 1H+ H₂O),3.75-4.2 (m, 2H), 3.95 (s, 3H), 4.75-5.0 (m, 1H), 7.2-7.4 (m, 2H),7.4-7.6 (m, 2H), 7.8 (s, 1H), 8.37 (s, 1H), 9.65 (s, 1H); Mass Spectrum:(M+H)⁺ 514; melting point 193° C.

EXAMPLE 35(2S)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol(Process (b))

N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine(500 mg, 1.05 mmol) and 4-dimethylaminopyridine (128 mg, 1.05 mmol) werestirred in acetonitrile (2.5 ml) and diisopropylethylamine (0.366 ml,2.10 mmol) was added. The mixture was cooled to 0° C. and a solution of(S)-(−)-2-acetoxypropionyl chloride (0.166 ml, 1.31 mmol) inacetonitrile (0.5 ml) was added drop-wise. The reaction mixture was thenstirred at this temperature for 0.5 hours. Water (1.0 ml) and potassiumhydroxide (0.641 ml of a 49% w/w solution in water) were added and themixture stirred at room temperature over night. The layers wereseparated and the organic layer diluted with ethyl acetate (2.5 ml).Water was added followed by glacial acetic acid (0.210 ml). The mixturewas stirred and partitioned. The organics were dried over magnesiumsulphate, filtered and concentrated under reduced pressure to give thetitle product (215 mg, 43%) as a white solid; ¹H NMR Spectrum: (DMSO d₆)1.19 (d, 3H), 1.48-1.75 (m, 2H), 1.94-2.13 (m, 2H), 3.21-3.53 (m, 2H),3.93 (s, 3H), 3.78-4.06 (m, 2H), 4.40-4.52 (m, 1H), 4.83-4.99 (m, 2H),7.28 (dd, 1H), 7.33 (s, 1H), 7.42-7.55 (m, 2H), 7.81 (s, 1H), 8.36 (s,1H), 9.62 (s, 1H); Mass Spectrum: (M+H)⁺ 475.

EXAMPLE 36N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-{[1-(3-methoxypropanoyl)piperidin-4-yl]oxy}quinazolin-4-amine(Process (b))

N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-aminewas coupled with 3-methoxypropionyl chloride using an analogous processto that described in Example 35 except that following addition of thewater and potassium hydroxide at the completion of the couplingreaction, the layers were separated directly and the product wasextracted and isolated as described in Example 35 to give the titleproduct; ¹H NMR Spectrum: (DMSO d₆) 1.59 (m, 1H); 1.69 (m, 1H); 2.04 (m,2H); 2.61 (t, 2H); 3.21 (s, 3H); 3.26 (m, 1H); 3.41 (m, 1H); 3.57 (t,2H); 3.77 (m, 1H); 3.95 (m, 4H); 4.90 (m, 1H); 7.29 (m, 1H); 7.35 (s,1H); 7.48 (m, 1H); 7.53 (m, 1H); 7.83 (s, 1H); 8.39 (s, 1H); 9.63 (s,1H). Mass Spectrum: (M+H)⁺ 489.

EXAMPLE 37 Pharmaceutical Compositions

The following illustrates representative pharmaceutical dosage forms ofthe invention as defined herein (the active ingredient being termed“Compound X”) which may be prepared, for therapeutic or prophylactic usein humans:

(a) Tablet I mg/tablet Compound X 100 Lactose Ph.Eur 182.75Croscarmellose sodium 12.0 Maize starch paste (5% w/v paste) 2.25Magnesium stearate 3.0 (b) Injection I (50 mg/ml) Compound X  5.0% w/v1M Sodium hydroxide solution 15.0% v/v 0.1M Hydrochloric acid (to adjustpH to 7.6) Polyethylene glycol 400 4.5% w/v Water for injection to 100%.

The above compositions may be prepared by conventional procedures wellknown in the pharmaceutical art. For example, Tablet I may be preparedby blending the components together and compressing the mixture into atablet.

1. A quinazoline derivative of the Formula I:

wherein: R¹ is selected from hydrogen, hydroxy, (1-6C)alkoxy,(2-6C)alkenyloxy, (2-6C)alkynyloxy, or from a group of the formula:Q²-X³- wherein X³ is a direct bond or is O, and Q² is (3-7C)cycloalkyl,(3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-6C)alkyl, heterocyclyl orheterocyclyl-(1-6C)alkyl, and wherein adjacent carbon atoms in any(2-6C)alkylene chain within a R¹ substituent are optionally separated bythe insertion into the chain of a group selected from O, S, SO, SO₂,N(R³), CO, CH(OR³), CON(R³), N(R³)CO, SO₂N(R³), N(R³)SO₂, CH═CH and C≡Cwherein R³ is hydrogen or (1-6C)alkyl, and wherein any CH₂═CH— or HC≡C—group within a R¹ substituent optionally bears at the terminal CH₂═ orHC≡ position a substituent selected from halogeno, carboxy, carbamoyl,(1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, amino-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl orfrom a group of the formula:Q³-X⁴- wherein X⁴ is a direct bond or is selected from CO and N(R⁴)CO,wherein R⁴ is hydrogen or (1-6C)alkyl, and Q³ is heterocyclyl orheterocyclyl-(1-6C)alkyl, and wherein any CH₂ or CH₃ group within a R¹substituent, other than a CH₂ group within a heterocyclyl ring,optionally bears on each said CH₂ or CH₃ group one or more halogeno or(1-6C)alkyl substituents or a substituent selected from hydroxy, cyano,amino, carboxy, carbamoyl, sulfamoyl, oxo, thioxo, (1-6C)alkoxy,(1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,(2-6C)alkanoyloxy, (2-6C)alkanoylamino,N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulfamoyl,N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino andN-(1-6C)alkyl-(1-6C)alkanesulfonylamino, or from a group of the formula:-X⁵-Q⁴ wherein X⁵ is a direct bond or is selected from O, S, SO, SO₂,N(R⁵), CO, CH(OR⁵), CON(R⁵), N(R⁵)CO, SO₂N(R⁵), N(R⁵)SO₂, C(R⁵)₂₋₀,C(R⁵)₂S and C(R⁵)₂N(R⁵), wherein R⁵ is hydrogen or (1-6C)alkyl, and Q⁴is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-6C)alkyl, heterocyclyl orheterocyclyl-(1-6C)alkyl, and wherein any heterocyclyl group within asubstituent on R¹ optionally bears one or more substituents, which maybe the same or different, selected from halogeno, trifluoromethyl,cyano, nitro, hydroxy, amino, carboxy, carbamoyl, formyl, mercapto,sulfamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy,(2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio,(1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, N-(1-6C)alkylsulfamoyl,N,N-di-[(1-6C)alkyl]sulfamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,(1-6C)alkanesulfonylamino, and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino,or from a group of the formula:-X⁶-R⁶ wherein X⁶ is a direct bond or is selected from O, N(R⁷) andC(O), wherein R⁶⁷ is hydrogen or (1-6C)alkyl, and R⁶ ishalogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, carboxy-(1-6C)alkyl,(1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl,(2-6C)alkanoylamino-(1-6C)alkyl, (1-6C)alkoxycarbonylamino-(1-6C)alkyl,carbamoyl-(1-6C)alkyl, N-(1-6C)alkylcarbamoyl-(1-6C)alkyl,N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl, (2-6C)alkanoyl-(1-6C)alkyl or(1-6C)alkoxycarbonyl-(1-6C)alkyl, and wherein any heterocyclyl groupwithin a substituent on R¹ optionally bears 1 or 2 oxo or thioxosubstituents; b is 1, 2, 3, 4 or 5; each R², which may be the same ordifferent, is selected from halogeno, cyano, nitro, hydroxy, amino,carboxy, carbamoyl, sulfamoyl, trifluoromethyl, (1-6C)alkyl,(2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy,(2-6C)alkynyloxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl,(1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,(1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,(1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino and agroup of the formula:-X⁷-R⁸ wherein X⁷ is a direct bond or is selected from O and N(R⁹),wherein R⁹ is hydrogen or (1-6C)alkyl, and R⁸ is halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,di-[(1-6C)alkyl]amino-(1-6C)alkyl, (2-6C)alkanoylamino-(1-6C)alkyl or(1-6C)alkoxycarbonylamino-(1-6C)alkyl; Q′ is piperidinyl; a is 0, 1, 2,3 or 4; each W, which may be the same or different, is selected fromhalogeno, trifluoromethyl, cyano, nitro, hydroxy, oxo, amino, formyl,mercapto, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylthio,(1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from agroup of the formula:-X⁸-R¹⁰ wherein X⁸ is a direct bond or is selected from O, CO, SO₂ andN(R¹¹), wherein R¹¹ is hydrogen or (1-6C)alkyl, and R¹⁰ ishalogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl,cyano-(1-6C)alkyl, amino-(1-6C)alkyl, N-(1-6C)alkylamino-(1-6C)alkyl orN,N-di-[(1-6C)alkyl]amino-(1-6C)alkyl; X¹ is selected from CO and SO₂;X² is a group of the formula:—(CR¹²R¹³)_(p)-(Q⁵)_(m)-(CR¹⁴R¹⁵)_(q)- wherein m is 0 or 1,p is 0, 1, 2,3 or 4 and q is 0, 1, 2, 3 or 4, each of R¹², R¹³, R¹⁴ and R¹⁵, whichmay be the same or different, is selected from hydrogen, (1-6C)alkyl,amino, (1-6C)alkylamino and di-[(1-6C)alkyl]amino, and Q⁵ is selectedfrom (3-7C)cycloalkylene and (3-7C)cycloalkenylene, and wherein any CH₂or CH₃ group within an X² group, optionally bears on each said CH₂ orCH₃ group one or more halogeno or (1-6C)alkyl substituents or asubstituent selected from hydroxy, cyano; amino, (1-6C)alkoxy,(1-6C)alkylamino and di-[(1-6C)alkyl]amino; Z is selected from hydroxy,amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxy,(1-6C)alkylsulfonyl, (1-6C)alkanesulfonylamino,N-(1-6C)alkyl-(1-6C)alkanesulfonylamino and a group of the formula:Q⁶-X⁹- wherein X⁹ is a direct bond or is selected from O, N(R¹⁶), SO₂and SO₂N(R¹⁶), wherein R¹⁶ is hydrogen or (1-6C)alkyl, and Q⁶ is(3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl orheterocyclyl-(1-4C)alkyl; provided that when X⁹ is a direct bond, Q⁶ isheterocyclyl, and provided that when m, p and q are all 0, then Z isheterocyclyl, and wherein adjacent carbon atoms in any (2-6C)alkylenechain within a Z substituent are optionally separated by the insertioninto the chain of a group selected from O, S, SO, SO₂, N(R¹⁷), Co, —C≡C—and —C≡C— wherein R¹⁷ is hydrogen or (1-6C)alkyl, and wherein andwherein any CH₂ or CH₃ group within any Z group, other than a CH₂ groupwithin a heterocyclyl ring, optionally bears on each said CH₂ or CH₃group one or more halogeno or (1-6C)alkyl substituents or a substituentselected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl,(2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio,(1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,(1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino,and wherein any heterocyclyl group within a Z substituent optionallybears one or more substitutents which may be the same or different,selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino,formyl, mercapto, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,(1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoyl,(2-6C)alkanoyloxy and from a group of the formula:-X¹⁰-R¹⁸ wherein X¹⁰ is a direct bond or is selected from O, CO, SO₂ andN(R¹⁹), wherein R¹⁹ is hydrogen or (1-4C)alkyl, and R¹⁸ ishalogeno-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl,cyano-(1-4C)alkyl, amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyl andN,N-di-[(1-4C)alkyl]amino-(1-4C)alkyl; provided that: when the 4-anilinogroup in Formula I is 4-bromo-2-fluoroanilino or4-chloro-2-fluoroanilino and R¹ is hydrogen or (1-3C)alkoxy, then a is 0and Z is selected from hydroxy, amino, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxy, (1-6C)alkylsulfonyl,(1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, anda group of the formula Q⁶-X⁹-; or a pharmaceutically acceptable salt, ora pharmaceutically acceptable ester thereof.
 2. A quinazoline derivativeof the Formula I, or a pharmaceutically acceptable salt, or apharmaceutically acceptable ester thereof, according to claim 1 wherein:R¹ is selected from hydrogen, hydroxy, (1-6C)alkoxy, (2-6C)alkenyloxy,(2-6C)alkynyloxy, or from a group of the formula:Q²-X³- wherein X³ is a direct bond or is O, and Q² is heterocyclyl orheterocyclyl-(1-6C)alkyl, and wherein adjacent carbon atoms in any(2-6C)alkylene chain within a R¹ substituent are optionally separated bythe insertion into the chain of a group selected from O, N(R³), CON(R³),N(R³)CO, CH═CH and C≡C wherein R³ is hydrogen or (1-6C)alkyl, andwherein any CH₂═CH— or HC≡C— group within a R¹ substituent optionallybears at the terminal CH₂═ or HC≡ position a substituent selected fromcarbamoyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl anddi-[(1-6C)alkyl]amino-(1-6C)alkyl and wherein any CH₂ or CH₃ groupwithin a R¹ substituent, other than a CH₂ group within a heterocyclylring, optionally bears on each said CH₂ or CH₃ group one or morehalogeno or (1-6C)alkyl substituents or a substituent selected fromhydroxy, amino, cyano, carbamoyl, (1-6C)alkoxy, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl andN,N-di-[(1-6C)alkyl]carbamoyl, or from a group of the formula-X⁵-Q⁴ wherein X⁵ is a direct bond or is selected from O, N(R⁵),CON(R⁵), N(R⁵)CO and C(R⁵)₂O, wherein R⁵ is hydrogen or (1-6C)alkyl, andQ⁴ is heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein anyheterocyclyl group within a substituent on R¹ optionally bears 1, 2 or 3substituents, which may be the same or different, selected fromhalogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (1-6C)alkyl,(2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, or from a group of theformula:X⁶-R⁶ wherein X⁶ is a direct bond or is selected from O and N(R⁷),wherein R⁷ is hydrogen or (1-6C)alkyl, and R⁶ is halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl anddi-[(1-6C)alkyl]amino-(1-6C)alkyl, and wherein any heterocyclyl groupwithin a substituent on R¹ optionally bears 1 or 12 oxo substituents. 3.A quinazoline derivative of the Formula I, or a pharmaceuticallyacceptable salt, or a pharmaceutically acceptable ester thereof,according to claim 1 wherein: R¹ is selected from hydrogen, hydroxy,(1-4C)alkoxy, hydroxy-(2-4C)alkoxy, (1-3C)alkoxy-(2-4C)alkoxy or from agroup of the formula:Q²-X³- wherein X³ is O, and Q² is azetidin-1-yl-(2-4C)alkyl,pyrrolidin-1-yl-(2-4C)alkyl, piperidino-(2-4C)alkyl,piperazino-(2-4C)alkyl or morpholino-(2-4C)alkyl, and wherein anyheterocyclyl group within a substituent on R¹ optionally bears 1, 2 or 3substituents, which may be the same or different, selected fromhalogeno, hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy,(1-4C)alkylsulfonyl, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, and(2-4C)alkanoyl, and wherein any heterocyclyl group within a substituenton R¹ optionally bears 1 oxo substituent.
 4. A quinazoline derivative ofthe Formula I, or a pharmaceutically acceptable salt, or apharmaceutically acceptable ester thereof, according to claim 1 whereinR¹ is (1-3C)alkoxy.
 5. A quinazoline derivative of the Formula I, or apharmaceutically acceptable salt, or a pharmaceutically acceptable esterthereof, according to claim 1 wherein: b is 1, 2 or 3; and each R²,which may be the same or different, is selected from fluoro, chloro,bromo, (1-4C)alkyl, (2-4C)alkenyl and (2-4C)alkynyl.
 6. A quinazolinederivative of the Formula I, or a pharmaceutically acceptable salt, or apharmaceutically acceptable ester thereof, according to claim 1 wherein:b is 1, 2 or 3 and one R² is at the meta (3-) position on the anilinogroup in Formula I and is halogeno.
 7. A quinazoline derivative of theFormula I, or a pharmaceutically acceptable salt, or a pharmaceuticallyacceptable ester thereof, according to claim 1 wherein the anilino groupat the 4-position on the quinazoline ring in the compound of Formula Iis selected from 3-chloro-2-bromoanilino, 3-chloro-2-fluoroanilino,3-ethynylanilino and 3-bromoanilino.
 8. A quinazoline derivative of theFormula I, or a pharmaceutically acceptable salt, or a pharmaceuticallyacceptable ester thereof, according to claim 1 wherein: X² is a group ofthe formula —(CR¹²R¹³)_(q)—(CR^(12aa)R^(13aa))—, wherein q is 1, 2 or 3,each of R¹², R¹³ and R^(13aa), which may be the same or different, isselected from hydrogen and (1-6C)alkyl, R^(12aa) is selected from amino,(1-6C)alkylamino and di-[(1-6C)alkyl]amino, and wherein any CH₂ or CH₃group within an X² group, optionally bears on each said CH₂ or CH₃ groupone or more halogeno substituents, and wherein any CH₂ group which isattached to 2 carbon atoms or any CH₃ group which is attached to acarbon atom within a X² substituent optionally bears on each said CH₂ orCH₃ group a substituent selected from hydroxy, amino, (1-6C)alkoxy,(1-6C)alkylamino and di-[(1-6C)alkyl]amino.
 9. A quinazoline derivativeof the Formula I, or a pharmaceutically acceptable salt, or apharmaceutically acceptable ester thereof, according to claim 1 wherein:X² is a group of the formula —(CR¹²R¹³)_(q)-, wherein q is 1, 2, 3 or 4,each of R¹² and R¹³, which may be the same or different, is selectedfrom hydrogen and (1-6C)alkyl, provided that at least one of the R¹² orR¹³ groups in X² is (1-6C)alkyl, and wherein any CH₂ or CH₃ group withinan X² group, optionally bears on each said CH₂ or CH₃ group one or morehalogeno substituents, and wherein any CH₂ group which is attached to 2carbon atoms or any CH₃ group which is attached to a carbon atom withina X² substituent optionally bears on each said CH₂ or CH₃ group asubstituent selected from hydroxy, and (1-6C)alkoxy.
 10. A quinazolinederivative of the Formula I, or a pharmaceutically acceptable salt, or apharmaceutically acceptable ester thereof, according to claim 1 wherein:X² is selected from a group of the formula —CH₂—, —CH₂CH₂—,—(CHR^(12a))-, —(CHR^(12a)CH₂)—, —(C(R^(12a))₂CH₂)—, —(CH₂C(R^(12a))₂)-and —(CH₂CHR^(12a))—, wherein each R^(12a), which may be the same ordifferent, is (1-4C)alkyl.
 11. A quinazoline derivative of the FormulaI, or a pharmaceutically acceptable salt, or a pharmaceuticallyacceptable ester thereof, according to claim 1 wherein: Z is selectedfrom hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,(1-6C)alkoxy, hydroxy-(2-6C)alkoxy, (1-4C)alkoxy-(2-6C)alkoxy and agroup of the formula:Q⁶-X⁹- wherein X⁹ is a direct bond and Q⁶ is heterocyclyl, and providedthat when m, p and q are all 0, then Z is heterocyclyl linked to X¹ by aring carbon atom, and wherein any heterocyclyl group in Z is selectedfrom azetidinyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl,1,4-dioxanyl, oxepanyl, pyrrolidinyl, morpholinyl, piperidinyl,homopiperidinyl, piperazinyl and homopiperazinyl, and wherein andwherein any CH₂ or CH₃ group within a Z group, other than a CH₂ groupwithin a heterocyclyl ring, optionally bears on each said CH₂ or CH₃group one or more halogeno or (1-4C)alkyl substituents or a substituentselected from hydroxy and (1-4C)alkoxy, and wherein any heterocyclylgroup within a Z substituent optionally bears one or more substitutentswhich may be the same or different, selected from halogeno,trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, (1-4C)alkyl,(1-4C)alkoxy, (1-4C)alkylsulfonyl, (1-4C)alkylamino,di-[(1-4C)alkyl]amino and (2-4C)alkanoyl.
 12. A quinazoline derivativeof the Formula I, or a pharmaceutically acceptable salt, or apharmaceutically acceptable ester thereof, according to claim 1 wherein:Z is hydroxy or (1-4C)alkoxy; and the sum of m+p+q is at least
 1. 13. Aquinazoline derivative of the Formula I, or a pharmaceuticallyacceptable salt, or a pharmaceutically acceptable ester thereof,according to claim 1 wherein: X² is selected from a group of the formula—CH₂—, —CH₂CH₂—, —(CHR^(12a))-, —(CHR^(12a)CH₂)—, —(C(R^(12a))₂CH₂)—,—(CH₂C(R^(12a))₂)- and —(CH₂CHR^(12a))—, wherein each R^(12a), which maybe the same or different, is (1-4C)alkyl; and Z is hydroxy or(1-4C)alkoxy.
 14. A quinazoline derivative of the Formula I, or apharmaceutically acceptable salt, or a pharmaceutically acceptable esterthereof, according to claim 1 wherein: Q¹ is piperidin-4-yl; a is 0 or1; and W is selected from halogeno, hydroxy, (1-3C)alkyl and(1-3C)alkoxy.
 15. A quinazoline derivative of the Formula I, or apharmaceutically acceptable salt, or a pharmaceutically acceptable esterthereof, according to claim 1 wherein X¹ is CO.
 16. A quinazolinederivative of the Formula I, or a pharmaceutically acceptable salt, or apharmaceutically acceptable ester thereof, according to claim 1 wherein:R¹ is selected from hydrogen, (1-6C)alkoxy, cyclopropyl-(1-4C)alkoxy,cyclobutyl-(1-4C)alkoxy, cyclopentyl-(1-4C)alkoxy,cyclohexyl-(1-6C)alkoxy, tetrahydrofuranyl-(1-4C)alkoxy andtetrahydropyranyl-(1-4C)alkoxy, and wherein any CH₂ or CH₃ group withina R¹ substituent optionally bears on each said CH₂ or CH₃ group one ormore halogeno substituents, or a substituent selected from hydroxy and(1-4C)alkoxy; b is 1, 2 or 3; each R², which may be the same ordifferent, is selected from halogeno, cyano, hydroxy, trifluoromethyl,(1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl and (1-4C)alkoxy; Q¹ ispiperidin-4-yl; a is 0, 1 or 2; each W, which may be the same ordifferent, is selected from halogeno, trifluoromethyl, hydroxy, oxo,(1-6C)alkyl, (1-6C)alkoxy, and from a group of the formula:-X⁸-R¹⁰ wherein X⁸ is a direct bond or is O, and R¹⁰ ishalogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl or (1-6C)alkoxy-(1-6C)alkyl;X¹ is CO; X² is a group selected from (3-6C)cycloalkylene, —CH₂—,—CH₂CH₂—, —CH₂CH₂CH₂—, —(CR¹²R¹³), —(CR¹²R¹³CH₂)— and —(CH₂CR¹²R¹³ )-,wherein each of R¹² and R¹³, which may be the same or different, isselected from hydrogen, (1-4C)alkyl, hydroxy-(1-4C)alkyl, and(1-3C)alkoxy-(1-4C)alkyl, provided that R¹² and R¹³ are not bothhydrogen, and wherein any CH₂ group within a (3-6C)cycloalkylene groupin X², optionally bears on each said CH₂ or group one or more(1-4C)alkyl substituents or a substituent selected from hydroxy,(1-4C)alkoxy, hydroxy-(1-4C)alkyl, and (1-3C)alkoxy-(1-4C)alkyl; and Zis selected from hydroxy and (1-4C)alkoxy; provided that: when the4-anilino group in Formula I is 4-bromo-2-fluoroanilino or4-chloro-2-fluoroanilino, R¹ is hydrogen or (1-3C)alkoxy, and X¹ is CO,then a is
 0. 17. A quinazoline derivative of the Formula I, or apharmaceutically acceptable salt, or a pharmaceutically acceptable esterthereof, according to claim 1 wherein: the 4-anilino group on thequinazoline ring in Formula I is selected from 3-chloro-4-fluoroanilino,3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 3-bromoanilino and3-ethynylanilino; R¹ is selected from (1-4C)alkoxy,hydroxy-(2-4C)alkoxy, (1-3C)alkoxy-(2-4C)alkoxy or from a group of theformula:Q²-X³- wherein X³ is O, and Q² is azetidin-1-yl-(2-4C)alkyl,pyrrolidin-1-yl-(2-4C)alkyl, piperidino-(2-4C)alkyl,piperazino-(2-4C)alkyl or morpholino-(2-4C)alkyl, and wherein anyheterocyclyl group within a substituent on R¹ optionally bears 1, 2 or 3substituents, which may be the same or different, selected fromhalogeno, hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylaminoand di-[(1-4C)alkyl]amino; Z is hydroxy or (1-4C)alkoxy; Q¹ ispiperidin-4-yl; a is 0 or 1; each W, which may be the same or differentis selected from hydroxy, (1-3C)alkyl and (1-3C)alkoxy; X¹ is CO; X² isselected from a group of the formula —(CHR¹²a)- and —(CH₂CHR^(12b))—,wherein R^(12a) is (1-4C)alkyl, and wherein R^(12b) is selected fromamino, (1-4C)alkylamino and di-[(1-4C)alkyl]-amino.
 18. A quinazolinederivative of the Formula I, or a pharmaceutically acceptable salt, or apharmaceutically acceptable ester thereof, according to claim 1 of theFormula Id:

wherein: R^(1b) is (1-4C)alkoxy, and wherein any CH₂ or CH₃ group withina R^(1b) substituent optionally bears on each said CH₂ or CH₃ group oneor more halogeno substituents, or any CH₂ or CH₃ group within a R¹ whichis not attached to an oxygen atom optionally bears on each said CH₂ orCH₃ group a substituent selected from hydroxy and (1-3C)alkoxy; X^(2b)is selected from a group of the formula —CH₂—, —CH₂CH₂—, —(CHR¹²)—,—(CHR¹²CH₂)— and —(CH₂CHR¹²)— wherein R¹² is selected from (1-3C)alkyl,hydroxy-(1-3C)alkyl and (1-3C)alkoxy-(1-3C)alkyl; and Z² is selectedfrom hydroxy, (1-3C)alkoxy, hydroxy-(2-3C)alkoxy,(1-3C)alkoxy-(2-3C)alkoxy, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,1,3-dioxolanyl, tetrahydropyranyl and 1,4-dioxanyl; and wherein anyheterocyclyl group within Z²-X^(2b) optionally bears 1 or 2substituents, which may be the same or different, selected from fluoro,chloro, hydroxy, (1-3C)alkyl, (1-3C)alkoxy and (2-3C)alkanoyl; or apharmaceutically acceptable salt, or a pharmaceutically acceptable esterthereof.
 19. A quinazoline derivative according to claim 18, or apharmaceutically acceptable salt, or a pharmaceutically acceptable esterthereof, wherein Z² is hydroxy and R¹² is (1-3C)alkyl;
 20. A quinazolinederivative according to claim 18, or a pharmaceutically acceptable salt,or a pharmaceutically acceptable ester thereof, wherein: R^(1b) is(1-3C)alkoxy; and the group Z²-X^(2b)- is selected from hydroxymethyl,methoxymethyl, (S)-1-hydroxyethyl, (R)-1-hydroxyethyl,(S)-1-methoxyethyl and (R)-1-methoxyethyl.
 21. A quinazoline derivativeof the Formula I according to claim 1 selected from:N-(3-chloro-2-fluorophenyl)-7-({1-[(dimethylamino)acetyl]piperidin-4-yl}oxy)-6-methoxyquinazolin-4-amine;N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2-methoxyethoxy)acetyl]piperidin-4-yl}oxy)quinazolin-4-amine;N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{[1-(methoxyacetyl)piperidin-4-yl]oxy}quinazolin-4-amine;2-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2-oxoethanol;N-(3-chloro-2-fluorophenyl)-7-{[1-(ethoxyacetyl)piperidin-4-yl]oxy}-6-methoxyquinazolin-4-amine;N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{[1-(3-methoxypropanoyl)piperidin-4-yl]oxy}quinazolin-4-amine;3-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-3-oxopropan-1-ol;(2S)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol;(2S,3S)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-3-methyl-1-oxopentan-2-ol;4-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2-methyl-4-oxobutan-2-ol;N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{[1-(tetrahydrofuran-2-ylcarbonyl)piperidin-4-yl]oxy}quinazolin-4-amine;3-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2,2-dimethyl-3-oxopropan-1-ol;(3R,5S)-1-acetyl-5-{[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]carbonyl}pyrrolidin-3-ol;andN-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(4-methylpiperazin-1-yl)acetyl]piperidin-4-yl}oxy)quinazolin-4-amine;and pharmaceutically acceptable salts, and pharmaceutically acceptableesters thereof.
 22. A quinazoline derivative of the Formula I accordingto claim 1 selected from:N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-{[1-(methoxyacetyl)piperidin-4-yl]oxy}quinazolin-4-amine;2-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2-oxoethanol;N-(3-chloro-2-fluorophenyl)-7-{[1-(ethoxyacetyl)piperidin-4-yl]oxy}-6-methoxyquinazolin-4-amine;(2S)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol;3-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2,2-dimethyl-3-oxopropan-1-ol;(2S)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-3,3-dimethyl-1-oxobutan-2-ol;N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{[1-(1-methyl-L-prolyl)piperidin-4-yl]oxy}quinazolin-4-amine;N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2S)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}oxy)quinazolin-4-amine;(2R)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol;N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2S)-2-methoxypropanoyl]piperidin-4-yl}oxy)quinazolin-4-amine;N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2R)-2-methoxypropanoyl]piperidin-4-yl}oxy)quinazolin-4-amine;(2R)-3-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2-(dimethylamino)-3-oxopropan-1-ol;(2S)-1-[4-({4-[(3-chloro-4-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol;(2S)-1-[4-({4-[3-bromoanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol;(2S)-1-[4-({4-[3-bromo-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol;(2R)-1-[4-({4-[3-bromo-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol;and(2R)-1-[4-({4-[3-bromoanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol;and pharmaceutically acceptable-salts, and pharmaceutically acceptableesters thereof.
 23. A quinazoline derivative of the Formula I accordingto claim 1, or a pharmaceutically acceptable salt thereof.
 24. Apharmaceutical composition which comprises a quinazoline derivative ofthe Formula I, or a pharmaceutically acceptable salt, or apharmaceutically acceptable ester thereof, according to claim 1, inassociation with a pharmaceutically acceptable diluent or carrier.25-29. (canceled)
 30. A method for producing an anti-proliferativeeffect in a warm-blooded animal, in need of such treatment whichcomprises administering to said animal an effective amount of aquinazoline derivative of the Formula I, or a pharmaceuticallyacceptable salt, or a pharmaceutically acceptable ester thereof, asdefined in claim
 1. 31. A method for the prevention or treatment ofthose tumours in a warm-blooded animal which are sensitive to inhibitionof EGFR tyrosine kinases, that are involved in the signal transductionsteps which lead to the proliferation and/or survival of tumour cellswhich comprises administering to said animal an effective amount of aquinazoline derivative of the Formula I, or a pharmaceuticallyacceptable salt, or a pharmaceutically acceptable ester thereof, asdefined in claim
 1. 32. A method for providing a selective EGFR tyrosinekinase inhibitory effect in a warm-blooded animal which comprisesadministering to said animal an effective amount of a quinazolinederivative of the Formula I, or a pharmaceutically acceptable salt, or apharmaceutically acceptable ester thereof, as defined in claim
 1. 33. Amethod for treating a cancer in a warm-blooded animal, in need of suchtreatment, which comprises administering to said animal an effectiveamount of a quinazoline derivative of the Formula I, or apharmaceutically acceptable salt, or a pharmaceutically acceptable esterthereof, as defined in claim
 1. 34. A process for the preparation of aquinazoline derivative of the Formula I as defined in claim 1 whichcomprises: Process (a): for the preparation of compounds of the FormulaI wherein X¹ is CO, the coupling of a quinazoline of the formula II or asalt thereof:

wherein R¹, R², W, a, b and Q¹ are as defined in claim 1 except that anyfunctional group is optionally protected with an acid of the formulaIII, or a reactive derivative thereof:Z-X²—COOH  III wherein Z and X² are as defined in claim 1, except thatany functional group is optionally protected; or Process (b) thereaction of a quinazoline of the formula II or a salt thereof, asdefined in relation to Process (a), with a compound of the formula IV:Z-X²-X¹-L¹  IV wherein L¹ is a displaceable group and Z, X¹ and X² areas defined in claim 1, except that any functional group is optionallyprotected; or Process (c) for the preparation of those quinazolinederivatives of the Formula I wherein Z is linked to X² by nitrogen, thereaction of a compound of the formula V:

wherein L² is a displaceable group and R¹, R², W, X¹, X², a, b and Q¹are as defined in claim 1, except that any functional group isoptionally protected, with a compound of the formula ZH, wherein Z is ashereinbefore defined, except that any functional group is optionallyprotected; or Process (d) for the preparation of those quinazolinederivatives which carry a mono- or di-(1-6C)alkylamino group, thereductive amination of the corresponding quinazoline derivative of theFormula I which contains an N—H group using formaldehyde or a(2-6C)alkanolaldehyde; or Process (e) for the preparation of thosequinazoline derivatives of the Formula I wherein R¹ is hydroxy, thecleavage of a quinazoline derivative of the Formula I wherein R¹ is a(1-6C)alkoxy group; or Process (f) for the preparation of thosequinazoline derivatives of the Formula I wherein R¹ is linked to thequinazoline ring by an oxygen atom, by coupling a compound of theFormula VI:

wherein R², W, X¹, X², Z, a, b and are as defined in claim 1 except thatany functional group is optionally protected with a compound of theformula R^(1′)OH, wherein the group R^(1′)O is one of the oxygen linkedgroups as defined for R¹ in claim 1, except that any functional group isoptionally protected; and thereafter, optionally (in any order): (i)converting a quinazoline derivative of the Formula I into anotherquinazoline derivative of the Formula I; (ii) removing any protectinggroup that is present; and (iii) forming a pharmaceutically acceptablesalt, or a pharmaceutically acceptable ester of the quinazolinederivative of the Formula I.
 35. A quinazoline derivative of the FormulaII:

wherein: R¹ is selected from hydrogen, hydroxy, (1-6C)alkoxy,(2-6C)alkenyloxy, (2-6C)alkynyloxy, or from a group of the formula:Q²-X³- wherein X³ is a direct bond or is O, and Q² is (3-7C)cycloalkyl,(3-7C)-cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-6C)alkyl, heterocyclyl or heterocycyl-(1-6C)alkyl,and wherein adjacent carbon atoms in any (2-6C)alkylene chain within aR¹ substituent are optionally separated by the insertion into the chainof a group selected from O, S, SO, SO₂, N(R³), CO, CH(OR³), CON(R³),N(R³)CO, SO₂N(R³), N(R³)SO₂, CH═CH and C≡C wherein R³ is hydrogen or(1-6C)alkyl, and wherein any CH₂═CH— or HC≡C— group within a R¹substituent optionally bears at the terminal CH₂═ or HC≡ position asubstituent selected from halogeno, carboxy, carbamoyl,(1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, amino-(1-6C)alkyl.(1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl orfrom, a group of the formula:Q³-X⁴- wherein X⁴ is a direct bond or is selected from CO and N(R⁴)CO,wherein R⁴ is hydrogen or (1-6C)alkyl, and Q³ is heterocycyl orheterocyclyl-(1-6C)alkyl, and wherein any CH₂ or CH₃ group within a R¹substituent, other than a CH₂ group within a heterocyclyl ring,optionally bears on each said CH₂ or CH₃ group one or more halogeno or(1-6C)alkyl substituents or a substituent selected from hydroxy, cyano,amino carboxy, carbamoyl, sulfamoyl, oxo, thioxo,(1-6C)alkoxy(1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]carbamoyl, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,(2-6C)alkanoyloxy, (2-6C)alkanoylamino,N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulfamoyl,N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino andN-(1-6C)alkyl-(1-6C)alkalesulfonylamino, or from a group of the formula:-X⁵-Q⁴ wherein X⁵ is a direct bond or is selected from O, S, SO, N(R⁵),CO, CH(OR⁵), CON(R⁵), N(R⁵)CO, SO₂N(R⁵), N(R⁵)SO₂, C(R⁵)₂O, C(R⁵)₂S andC(R⁵)₂N(R⁵), wherein R⁵ is hydrogen or (1-6C)alkyl and Q₄ is(3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-6C)alkyl, heterocyclyl orheterocyclyl-(1-6C)alkyl, and wherein any heterocyclyl group within asubstituent on R¹ optionally bears one or more substituents, which maybe the same or different, selected from halogeno, trifluoromethyl,cyano, nitro, hydroxy, amino, carboxy, carbamoyl, formyl, mercapto,sulfamoyl, (1-6C)alkyl, (2-8C)alkenyl. (2-8C)alkynyl, (1-6C)alkoxy.(2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio,(1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino. (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl.N,N-di-[(1-6C)alkyl]carbamoyl, N-(1-6C)alkylsulfamoyl,N,N-di-[(1-6C)alkyl]sulfamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino.N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,(1-6C)alkanesulfonylamino, and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino,or from a group of the formula:-X⁶-R⁶ wherein X⁶ is a direct bond or is selected from O, N(R⁷) andC(O), wherein R⁷ is hydrogen or (1-6C)alkyl, and R⁶ ishalogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, carboxy-(1-6C)alkyl,(1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl,(2-6C)alkanoylamino-(1-6C)alkyl, (1-6C)alkoxycarbonylamino-(1-6C)alkyl,carbamoyl-(1-6C)alkyl, N-(1-6C)alkylcarbamoyl-(1-6C)alkylN,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl, (2-6C)alkanoyl-(1-6C)alkyl or(1-6C)alkoxycarbonyl-(1-6C)alkyl, and wherein any heterocyclyl groupwithin a substituent on R¹ optionally bears 1 or 2 oxo or thioxosubstituents; Q¹ is piperidinyl; a is 0, 1, 2, 3 or 4; each W, which maybe the same or different, is selected from halogeno, trifluoromethyl,cyano, nitro, hydroxy, oxo, amino, formyl, mercapto, (1-6C)alkyl,(1-6C)alkoxy, (1-6C)alkylthio. (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoyl,(2-6C)alkanoyloxy and from a group of the formula:-X⁸-R¹⁰ wherein X⁸ is a direct bond or is selected from O, CO, SO₂ andN(R¹¹) wherein R¹¹ is hydrogen or (1-6C)alkyl, and R¹⁰ ishalogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl,cyano-(1-6C)alkyl, amino-(1-6C)alkyl. N-(1-6C)alkylamino-(1-6C)alkyl orN,N-di-[(1-6C)alkyl]amino-(1-6C)alkyl; R^(2c) and R^(2d), which may bethe same or different are halogeno; or a salt thereof.
 36. The methodaccording to claim 33 wherein said cancer is selected from lung cancer,non-small cell lung cancer, breast cancer, head and neck cancer, gastriccancer, colorectal cancer and ovarian cancer.
 37. A method for treatingpsoriasis in a warm-blooded animal in need of such treatment, whichcomprises administering to said animal an effective amount of aquinazoline derivative of the Formula I, or a pharmaceuticallyacceptable salt, or a pharmaceutically acceptable ester thereof, asdefined in claim 1.